rs28730853

Variant names:

• chr2-73451489-G-T
• rs28730853
• NM_001378454.1:c.4962G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):​c.4962G>T​(p.Lys1654Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,614,006 control chromosomes in the GnomAD database, including 935 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (125 hom., cov: 32)
  • Exomes 𝑓: 0.013 (810 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.250
• Publications: 8 publications found

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015060306).
• BP6: Variant 2-73451489-G-T is Benign according to our data. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451489-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.4962G>T	p.Lys1654Asn	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.4962G>T	p.Lys1654Asn	missense_variant	Exon 8 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.4962G>T	p.Lys1654Asn	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3344 AN: 152088 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0876

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00621

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0323 AC: 8044 AN: 248846 AF XY: 0.0252

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00189

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.0247

GnomAD4 exome AF: 0.0126 AC: 18473 AN: 1461800 Hom.: 810 Cov.: 39 AF XY: 0.0117 AC XY: 8475 AN XY: 727202

African (AFR) AF: 0.0302 AC: 1012 AN: 33470

American (AMR) AF: 0.168 AC: 7491 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26136

East Asian (EAS) AF: 0.00801 AC: 318 AN: 39698

South Asian (SAS) AF: 0.00361 AC: 311 AN: 86256

European-Finnish (FIN) AF: 0.0183 AC: 975 AN: 53408

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00681 AC: 7569 AN: 1111972

Other (OTH) AF: 0.0116 AC: 702 AN: 60392

GnomAD4 genome AF: 0.0221 AC: 3360 AN: 152206 Hom.: 125 Cov.: 32 AF XY: 0.0235 AC XY: 1750 AN XY: 74420

African (AFR) AF: 0.0309 AC: 1281 AN: 41522

American (AMR) AF: 0.0880 AC: 1346 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5182

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4822

European-Finnish (FIN) AF: 0.0212 AC: 225 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00621 AC: 422 AN: 67998

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0106 Hom.: 69

Bravo AF: 0.0295

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.0294 AC: 109

ESP6500EA AF: 0.00694 AC: 57

ExAC AF: 0.0271 AC: 3273

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs28730853 in Alstrom syndrome yet. -

not specified Benign:2

Oct 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Lys1653Asn in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 19.52% (2252/11536) of Latino chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs28730853). -

not provided Benign:2

Aug 10, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Monogenic diabetes Benign:1

Jan 25, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BP4 (REVEL score 0.033 + 7 predictors, not using PP3/2 predictors), BA1 (17.7% in gnomAD latino, 3% overall MAF), BS2 (652 homozygotes in gnomAD), BP1 (missense in gene with truncating cause disease): Benign; likely in cis with the other ALMS1 variant -

Cardiovascular phenotype Benign:1

Dec 28, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.3
DANN	Benign	0.95
DEOGEN2	Benign	0.030	T;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.25
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.50	T;T;T
Vest4		0.044
ClinPred		0.015	T
GERP RS		-0.87
Varity_R		0.033
gMVP		0.25
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28730853; hg19: chr2-73678616;