rs112034360

Variant names:

• chr2-73450421-A-G
• rs112034360
• NM_001378454.1:c.3894A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378454.1(ALMS1):​c.3894A>G​(p.Gln1298Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.053 in 1,612,926 control chromosomes in the GnomAD database, including 2,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (305 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2310 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.36
• Publications: 5 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-73450421-A-G is Benign according to our data. Variant chr2-73450421-A-G is described in ClinVar as Benign. ClinVar VariationId is 383756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

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.3894A>G	p.Gln1298Gln	synonymous	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.3894A>G	p.Gln1298Gln	synonymous	Exon 8 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.3894A>G	p.Gln1298Gln	synonymous	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.3768A>G	p.Gln1256Gln	synonymous	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.3513A>G	p.Gln1171Gln	synonymous	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.0582 AC: 8796 AN: 151030 Hom.: 305 Cov.: 32

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0292

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0906

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0513

GnomAD2 exomes AF: 0.0453 AC: 11284 AN: 249262 AF XY: 0.0436

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0833

Gnomad NFE exome AF: 0.0586

Gnomad OTH exome AF: 0.0500

GnomAD4 exome AF: 0.0525 AC: 76674 AN: 1461780 Hom.: 2310 Cov.: 40 AF XY: 0.0512 AC XY: 37217 AN XY: 727192

African (AFR) AF: 0.0702 AC: 2351 AN: 33468

American (AMR) AF: 0.0247 AC: 1104 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 848 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0116 AC: 1003 AN: 86256

European-Finnish (FIN) AF: 0.0820 AC: 4381 AN: 53418

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5766

European-Non Finnish (NFE) AF: 0.0576 AC: 64051 AN: 1111934

Other (OTH) AF: 0.0473 AC: 2855 AN: 60390

GnomAD4 genome AF: 0.0582 AC: 8796 AN: 151146 Hom.: 305 Cov.: 32 AF XY: 0.0579 AC XY: 4277 AN XY: 73844

African (AFR) AF: 0.0749 AC: 3073 AN: 41006

American (AMR) AF: 0.0309 AC: 468 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 101 AN: 3458

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5150

South Asian (SAS) AF: 0.0128 AC: 61 AN: 4778

European-Finnish (FIN) AF: 0.0906 AC: 949 AN: 10474

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0593 AC: 4023 AN: 67838

Other (OTH) AF: 0.0508 AC: 107 AN: 2106

Alfa AF: 0.0596 Hom.: 147

Bravo AF: 0.0533

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0493

EpiControl AF: 0.0504

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Alstrom syndrome (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0040
DANN	Benign	0.15
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs112034360; hg19: chr2-73677548; COSMIC: COSV52502774; COSMIC: COSV52502774;