rs183390773

Variant names:

• chr2-73424610-T-C
• rs183390773
• NM_001378454.1:c.945T>C

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.945T>C​(p.Ser315Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,020 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.621
• 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-73424610-T-C is Benign according to our data. Variant chr2-73424610-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.621 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (174/152306) while in subpopulation NFE AF = 0.00163 (111/68024). AF 95% confidence interval is 0.00139. There are 0 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.945T>C	p.Ser315Ser	synonymous	Exon 5 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.945T>C	p.Ser315Ser	synonymous	Exon 5 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.945T>C	p.Ser315Ser	synonymous	Exon 5 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.819T>C	p.Ser273Ser	synonymous	Exon 4 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.495T>C	p.Ser165Ser	synonymous	Exon 3 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00129 AC: 322 AN: 249042 AF XY: 0.00119

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000929

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00150 AC: 2198 AN: 1461714 Hom.: 2 Cov.: 31 AF XY: 0.00149 AC XY: 1084 AN XY: 727150

African (AFR) AF: 0.000478 AC: 16 AN: 33478

American (AMR) AF: 0.00125 AC: 56 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00170 AC: 1895 AN: 1111982

Other (OTH) AF: 0.00129 AC: 78 AN: 60386

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74468

African (AFR) AF: 0.000241 AC: 10 AN: 41564

American (AMR) AF: 0.00118 AC: 18 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00109

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Alstrom syndrome (3)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.59
PhyloP100		0.62
Mutation Taster		=99/1	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: rs183390773; hg19: chr2-73651738; COSMIC: COSV100043898;