chr2-73600754-C-T

Variant names:

• chr2-73600754-C-T
• rs147831309
• NM_001378454.1:c.11745C>T

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.11745C>T​(p.Ser3915Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,614,058 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (14 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.41
• 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=-0.69).
• BP6: Variant 2-73600754-C-T is Benign according to our data. Variant chr2-73600754-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 391448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00133 (203/152198) while in subpopulation SAS AF = 0.00312 (15/4810). AF 95% confidence interval is 0.00192. There are 4 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.11745C>T	p.Ser3915Ser	synonymous	Exon 18 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.11745C>T	p.Ser3915Ser	synonymous	Exon 18 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.11745C>T	p.Ser3915Ser	synonymous	Exon 18 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.11619C>T	p.Ser3873Ser	synonymous	Exon 17 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.11364C>T	p.Ser3788Ser	synonymous	Exon 16 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152080 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00189 AC: 474 AN: 250250 AF XY: 0.00203

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00143 AC: 2087 AN: 1461860 Hom.: 14 Cov.: 31 AF XY: 0.00158 AC XY: 1149 AN XY: 727226

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00121 AC: 54 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 431 AN: 26136

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

South Asian (SAS) AF: 0.00405 AC: 349 AN: 86250

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53420

Middle Eastern (MID) AF: 0.00745 AC: 43 AN: 5768

European-Non Finnish (NFE) AF: 0.000933 AC: 1037 AN: 1111990

Other (OTH) AF: 0.00240 AC: 145 AN: 60396

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152198 Hom.: 4 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74408

African (AFR) AF: 0.0000482 AC: 2 AN: 41528

American (AMR) AF: 0.00118 AC: 18 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00312 AC: 15 AN: 4810

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68026

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00205 Hom.: 0

Bravo AF: 0.00128

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Alstrom syndrome (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.4
DANN	Benign	0.55
PhyloP100		-1.4
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: rs147831309; hg19: chr2-73827881;