rs17009061

Variant names:

• chr2-73452313-G-A
• rs17009061
• NM_001378454.1:c.5786G>A

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.5786G>A​(p.Arg1929Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,848 control chromosomes in the GnomAD database, including 920 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1929W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (125 hom., cov: 32)
  • Exomes 𝑓: 0.013 (795 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.06
• Publications: 7 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=0.0014262199).
• BP6: Variant 2-73452313-G-A is Benign according to our data. Variant chr2-73452313-G-A is described in ClinVar as Benign. ClinVar VariationId is 389387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.5786G>A	p.Arg1929Gln	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.5786G>A	p.Arg1929Gln	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.5786G>A	p.Arg1929Gln	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3359 AN: 151936 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0870

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00649

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.0321 AC: 7996 AN: 249024 AF XY: 0.0250

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00189

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.0247

GnomAD4 exome AF: 0.0128 AC: 18754 AN: 1461794 Hom.: 795 Cov.: 38 AF XY: 0.0118 AC XY: 8616 AN XY: 727194

African (AFR) AF: 0.0301 AC: 1008 AN: 33476

American (AMR) AF: 0.166 AC: 7411 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26132

East Asian (EAS) AF: 0.00806 AC: 320 AN: 39698

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

European-Finnish (FIN) AF: 0.0184 AC: 983 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00710 AC: 7894 AN: 1111966

Other (OTH) AF: 0.0121 AC: 732 AN: 60392

GnomAD4 genome AF: 0.0222 AC: 3374 AN: 152054 Hom.: 125 Cov.: 32 AF XY: 0.0236 AC XY: 1755 AN XY: 74322

African (AFR) AF: 0.0309 AC: 1281 AN: 41462

American (AMR) AF: 0.0875 AC: 1337 AN: 15278

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

East Asian (EAS) AF: 0.00291 AC: 15 AN: 5154

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00649 AC: 441 AN: 67972

Other (OTH) AF: 0.0171 AC: 36 AN: 2106

Alfa AF: 0.0127 Hom.: 138

Bravo AF: 0.0295

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.0292 AC: 110

ESP6500EA AF: 0.00707 AC: 58

ExAC AF: 0.0269 AC: 3251

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00551

ClinVar

Significance: 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

- -

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: 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 rs17009061 in Alstrom syndrome yet. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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.Arg1928Gln in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 19.32% (2222/11500) of Latino chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs17009061). -

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 0.039 + 7 predictors), BS1 (17.7% MAF in gnomAD Latino, overall MAF 3%), BA1 (641 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	0.057
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.6
DANN	Benign	0.66
DEOGEN2	Benign	0.015	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00026	N
LIST_S2	Benign	0.40	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		2.1
PrimateAI	Benign	0.22	T
Sift4G	Benign	1.0	T;T;T
Vest4		0.12
ClinPred		0.0011	T
GERP RS		2.0
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.039
gMVP		0.019
Mutation Taster		=100/0	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: rs17009061; hg19: chr2-73679440;