rs28730853

chr2-73451489-G-T

Variant summary

Our verdict is Benign. Variant got -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. 10/15 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:8
• Conservation: PhyloP100: -0.250

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]

ACMG classification

Verdict is Benign. Variant got -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 ClinVar as [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/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.4962G>T	p.Lys1654Asn	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.4965G>T	p.Lys1655Asn	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.4962G>T	p.Lys1654Asn	missense_variant	8/23	1	NM_001378454.1	P3

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

GnomAD3 exomes AF: 0.0323 AC: 8044 AN: 248846 Hom.: 641 AF XY: 0.0252 AC XY: 3399 AN XY: 135080

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 SAS exome AF: 0.00333

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

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00801

Gnomad4 SAS exome AF: 0.00361

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.00681

Gnomad4 OTH exome AF: 0.0116

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

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.0880

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.0212

Gnomad4 NFE AF: 0.00621

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00792 Hom.: 25

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Benign:3

Likely benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 10, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2018

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
MutationTaster	Benign	1.0	N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs28730853; hg19: chr2-73678616;