2-73385824-C-T

Variant names:

• chr2-73385824-C-T
• rs539250179
• ENST00000484298.5:c.-45C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_015120.4(ALMS1):​c.-45C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 678,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: ALMS1 NM_015120.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ENSG00000285068 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000595 (9/151236) while in subpopulation SAS AF = 0.00125 (6/4790). AF 95% confidence interval is 0.000545. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_015120.4	c.-45C>T		5_prime_UTR_variant	Exon 1 of 23		NP_055935.4
ALMS1	NM_001378454.1	c.-45C>T		upstream_gene_variant		ENST00000613296.6	NP_001365383.1
LOC105374804	XR_007087045.1	n.-143G>A		upstream_gene_variant
LOC105374804	XR_007087053.1	n.-143G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.-45C>T		upstream_gene_variant		1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.0000596 AC: 9 AN: 151128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000536 AC: 55 AN: 102618 AF XY: 0.000620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000461

Gnomad ASJ exome AF: 0.000166

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000305

GnomAD4 exome AF: 0.000265 AC: 140 AN: 527720 Hom.: 0 Cov.: 5 AF XY: 0.000377 AC XY: 107 AN XY: 284168

African (AFR) AF: 0.0000673 AC: 1 AN: 14864

American (AMR) AF: 0.0000307 AC: 1 AN: 32542

Ashkenazi Jewish (ASJ) AF: 0.000219 AC: 4 AN: 18280

East Asian (EAS) AF: 0.0000640 AC: 2 AN: 31262

South Asian (SAS) AF: 0.00218 AC: 124 AN: 56878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2358

European-Non Finnish (NFE) AF: 0.0000130 AC: 4 AN: 307990

Other (OTH) AF: 0.000135 AC: 4 AN: 29560

GnomAD4 genome AF: 0.0000595 AC: 9 AN: 151236 Hom.: 0 Cov.: 32 AF XY: 0.0000946 AC XY: 7 AN XY: 73986

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67272

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-2.0
PromoterAI		0.11	Neutral
Mutation Taster		=287/13	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: rs539250179; hg19: chr2-73612952;