rs142611294

Variant names:

• chr2-73490701-A-G
• rs142611294
• NM_001378454.1:c.8742A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378454.1(ALMS1):​c.8742A>G​(p.Val2914Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000812 in 1,614,208 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (4 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0140
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-73490701-A-G is Benign according to our data. Variant chr2-73490701-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.014 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00435 (663/152340) while in subpopulation AFR AF = 0.0152 (634/41580). AF 95% confidence interval is 0.0143. There are 2 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.8742A>G	p.Val2914Val	synonymous	Exon 10 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.8742A>G	p.Val2914Val	synonymous	Exon 10 of 23	NP_055935.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.8742A>G	p.Val2914Val	synonymous	Exon 10 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.8616A>G	p.Val2872Val	synonymous	Exon 9 of 22	ENSP00000478155.1
	ALMS1	ENST00000423048.5	TSL:1	n.3030+543A>G		intron	N/A	ENSP00000399833.1

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 660 AN: 152218 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00120 AC: 299 AN: 249498 AF XY: 0.000983

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000443 AC: 648 AN: 1461868 Hom.: 4 Cov.: 33 AF XY: 0.000378 AC XY: 275 AN XY: 727232

African (AFR) AF: 0.0144 AC: 482 AN: 33480

American (AMR) AF: 0.000939 AC: 42 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1112000

Other (OTH) AF: 0.00109 AC: 66 AN: 60396

GnomAD4 genome AF: 0.00435 AC: 663 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00422 AC XY: 314 AN XY: 74490

African (AFR) AF: 0.0152 AC: 634 AN: 41580

American (AMR) AF: 0.00131 AC: 20 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00213 Hom.: 1

Bravo AF: 0.00468

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Alstrom syndrome (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		0.014
Mutation Taster		=100/0	polymorphism

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: rs142611294; hg19: chr2-73717828;