rs28730854

chr2-73452829-C-Achr2-73452829-C-Gchr2-73452829-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001378454.1(ALMS1):c.6302C>A(p.Ser2101Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S2101S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.343

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-73452829-C-A is Pathogenic according to our data. Variant chr2-73452829-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 871762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73452829-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.6302C>A	p.Ser2101Ter	stop_gained	8/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.6305C>A	p.Ser2102Ter	stop_gained	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.6302C>A	p.Ser2101Ter	stop_gained	8/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247674

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134542

show subpopulations

Gnomad AFR exome

AF:

0.000198

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461452

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change creates a premature translational stop signal (p.Ser2102*) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). This variant is present in population databases (rs28730854, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 17594715, 30488743). ClinVar contains an entry for this variant (Variation ID: 871762). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Apr 10, 2022	The c.6305C>A;p.(Ser2102) variant creates a premature translational stop signal in the ALMS1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 871762; PMID: 30488743; 30064963; 17594715) - PS4. The variant is present at low allele frequencies population databases (rs28730854 – gnomAD 0.0004602%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Ser2102) was detected in trans with a pathogenic variant (PMID: 30488743; 30064963; 17594715) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2024	Variant summary: ALMS1 c.6299C>A (p.Ser2100X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2e-05 in 247674 control chromosomes. c.6299C>A has been reported in the literature in at-least one individual affected with Alstrom Syndrome (example, Bahena_2021). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34148116). ClinVar contains an entry for this variant (Variation ID: 871762). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 19, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17594715, 31106028, 29302074, 30488743, 30064963) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2021

The p.S2102* pathogenic mutation (also known as c.6305C>A), located in coding exon 8 of the ALMS1 gene, results from a C to A substitution at nucleotide position 6305. This changes the amino acid from a serine to a stop codon within coding exon 8. This mutation has been reported in the compound heterozygous state with other alterations which are expected to be pathogenic or likely pathogenic in several individuals with Alstrom syndrome or related features (Marshall JD et al. Hum Mutat, 2007 Nov;28:1114-23; Citton V et al. J Neuroradiol, 2016 Jun;43:195-9; Han JC et al. J Clin Endocrinol Metab, 2018 07;103:2707-2719; Hu H et al. Mol Psychiatry, 2019 07;24:1027-1039; Wang P et al. Transl Vis Sci Technol, 2019 Mar;8:21). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.28

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

0.13

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.18

MutationTaster

Benign

1.0

A;A;A

Vest4

0.72

GERP RS

3.4

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over