2-73572759-C-T

Variant names:

• chr2-73572759-C-T
• rs1473611414
• NM_001378454.1:c.10882C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001378454.1(ALMS1):​c.10882C>T​(p.Arg3628*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,806 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.44
• Publications: 1 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: Pathogenic. The variant received 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 2-73572759-C-T is Pathogenic according to our data. Variant chr2-73572759-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 434136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.10882C>T	p.Arg3628*	stop_gained	Exon 16 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.10882C>T	p.Arg3628*	stop_gained	Exon 16 of 23	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.10882C>T	p.Arg3628*	stop_gained	Exon 16 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.10756C>T	p.Arg3586*	stop_gained	Exon 15 of 22	ENSP00000478155.1
	ALMS1	ENST00000423048.5	TSL:1	n.*1301C>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249160 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Pathogenic:3

Mar 21, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 434136). This premature translational stop signal has been observed in individual(s) with ALMS1-related conditions (PMID: 15689433, 24400638). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg3629*) 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). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Dec 04, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the compound heterozygous state with a pathogenic variant on the opposite allele (in trans) in multiple unrelated individuals with Alstrom Syndrome and in the homozygous state with a pathogenic variant on the opposite allele (in trans) in an individual with Bardet-Biedl syndrome in the published literature (Bond et al., 2005; Minton et al., 2006; Sathya Priya et al., 2015; Brofferio et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar as pathogenic (ClinVar Variant ID# 434136; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15689433, 24400638, 28610912, 16720663, 22773737)

Retinal dystrophy Pathogenic:1

Jan 01, 2011

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bardet-Biedl syndrome Pathogenic:1

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		1.4
Vest4		0.74
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1473611414; hg19: chr2-73799886;