2-73385903-T-TGGAGGA

Position:

• chr2-73385903-T-TGGAGGA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BA1

The NM_001378454.1(ALMS1):​c.69_74dup​(p.Glu27_Glu28dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.059 (291 hom., cov: 0)
  • Exomes 𝑓: 0.063 (154 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:12
• Conservation: PhyloP100: 0.369

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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-T-TGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218713.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=5, Benign=6}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.69_74dup	p.Glu27_Glu28dup	inframe_insertion	1/23	ENST00000613296.6
ALMS1	NM_015120.4	c.69_74dup	p.Glu27_Glu28dup	inframe_insertion	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.69_74dup	p.Glu27_Glu28dup	inframe_insertion	1/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 8536 AN: 143400 Hom.: 292 Cov.: 0

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.0755

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.0603

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0595

GnomAD3 exomes AF: 0.0668 AC: 5566 AN: 83366 Hom.: 129 AF XY: 0.0657 AC XY: 2870 AN XY: 43654

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.0629

Gnomad SAS exome AF: 0.0837

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0477

GnomAD4 exome AF: 0.0632 AC: 35210 AN: 557130 Hom.: 154 Cov.: 0 AF XY: 0.0645 AC XY: 19197 AN XY: 297462

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.0554

Gnomad4 EAS exome AF: 0.0749

Gnomad4 SAS exome AF: 0.0967

Gnomad4 FIN exome AF: 0.0494

Gnomad4 NFE exome AF: 0.0566

Gnomad4 OTH exome AF: 0.0607

GnomAD4 genome AF: 0.0594 AC: 8530 AN: 143504 Hom.: 291 Cov.: 0 AF XY: 0.0622 AC XY: 4327 AN XY: 69588

Gnomad4 AFR AF: 0.0227

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.0698

Gnomad4 EAS AF: 0.0753

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0617

Gnomad4 NFE AF: 0.0672

Gnomad4 OTH AF: 0.0589

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alstrom syndrome Uncertain:5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 12, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55889738; hg19: chr2-73613031;