rs139512700

Variant names:

• chr2-73424847-T-C
• rs139512700
• NM_001378454.1:c.1182T>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.1182T>C​(p.Tyr394Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000708 in 1,607,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.05
• 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, 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=-0.94).
• BP6: Variant 2-73424847-T-C is Benign according to our data. Variant chr2-73424847-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00338 (515/152338) while in subpopulation AFR AF = 0.0113 (469/41570). AF 95% confidence interval is 0.0104. There are 3 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown 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.1182T>C	p.Tyr394Tyr	synonymous	Exon 5 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.1182T>C	p.Tyr394Tyr	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.1182T>C	p.Tyr394Tyr	synonymous	Exon 5 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.1056T>C	p.Tyr352Tyr	synonymous	Exon 4 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.732T>C	p.Tyr244Tyr	synonymous	Exon 3 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152220 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000949 AC: 233 AN: 245436 AF XY: 0.000737

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000646

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000675

GnomAD4 exome AF: 0.000428 AC: 623 AN: 1455512 Hom.: 1 Cov.: 32 AF XY: 0.000375 AC XY: 271 AN XY: 723124

African (AFR) AF: 0.0133 AC: 443 AN: 33266

American (AMR) AF: 0.000722 AC: 32 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 85364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5724

European-Non Finnish (NFE) AF: 0.0000875 AC: 97 AN: 1108102

Other (OTH) AF: 0.000782 AC: 47 AN: 60086

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74498

African (AFR) AF: 0.0113 AC: 469 AN: 41570

American (AMR) AF: 0.00235 AC: 36 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00182 Hom.: 1

Bravo AF: 0.00378

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.69
DANN	Benign	0.25
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs139512700; hg19: chr2-73651975;