2-73572341-A-G

Variant names:

• chr2-73572341-A-G
• rs28730858
• NM_001378454.1:c.10464A>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.10464A>G​(p.Val3488Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,608,156 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V3488V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.637
• 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=-0.6).
• BP6: Variant 2-73572341-A-G is Benign according to our data. Variant chr2-73572341-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.637 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00271 (413/152304) while in subpopulation AFR AF = 0.00969 (403/41570). AF 95% confidence interval is 0.00891. There are 3 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.10464A>G	p.Val3488Val	synonymous	Exon 16 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.10464A>G	p.Val3488Val	synonymous	Exon 16 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.10464A>G	p.Val3488Val	synonymous	Exon 16 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.10338A>G	p.Val3446Val	synonymous	Exon 15 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000423048.5	TSL:1	n.*883A>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152186 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000632 AC: 154 AN: 243560 AF XY: 0.000439

Gnomad AFR exome AF: 0.00922

Gnomad AMR exome AF: 0.000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000258 AC: 375 AN: 1455852 Hom.: 3 Cov.: 31 AF XY: 0.000209 AC XY: 151 AN XY: 723846

African (AFR) AF: 0.00936 AC: 310 AN: 33126

American (AMR) AF: 0.000273 AC: 12 AN: 43886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000472 AC: 4 AN: 84790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109676

Other (OTH) AF: 0.000666 AC: 40 AN: 60080

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152304 Hom.: 3 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74476

African (AFR) AF: 0.00969 AC: 403 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000951 Hom.: 0

Bravo AF: 0.00286

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.85
DANN	Benign	0.65
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28730858; hg19: chr2-73799468;