rs17009061

chr2-73452313-G-A

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.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. 10/15 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:8
• Conservation: PhyloP100: 2.06

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=0.0014262199).
• BP6: Variant 2-73452313-G-A is Benign according to our data. Variant chr2-73452313-G-A is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.5786G>A	p.Arg1929Gln	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.5789G>A	p.Arg1930Gln	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.5786G>A	p.Arg1929Gln	missense_variant	8/23	1	NM_001378454.1	P3

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

GnomAD3 exomes AF: 0.0321 AC: 7996 AN: 249024 Hom.: 628 AF XY: 0.0250 AC XY: 3381 AN XY: 135092

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 SAS exome AF: 0.00333

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

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00806

Gnomad4 SAS exome AF: 0.00361

Gnomad4 FIN exome AF: 0.0184

Gnomad4 NFE exome AF: 0.00710

Gnomad4 OTH exome AF: 0.0121

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

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.0875

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.00649

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.00910 Hom.: 38

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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 rs17009061 in Alstrom syndrome yet. -

not specified Benign:2

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

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 0.039 + 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 -

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	0.057
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
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	1.0	T;T;T
Vest4		0.12
ClinPred		0.0011	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.039
gMVP		0.019

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: rs17009061; hg19: chr2-73679440;