2-73385823-TCCC-TC

Variant names:

• chr2-73385823-TCC-T
• rs764473588
• ENST00000484298.5:c.-40_-39delCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015120.4(ALMS1):​c.-40_-39delCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 513,352 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: ALMS1 NM_015120.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_015120.4	c.-40_-39delCC		5_prime_UTR_variant	Exon 1 of 23		NP_055935.4
ALMS1	NM_001378454.1	c.-45_-44delCC		upstream_gene_variant		ENST00000613296.6	NP_001365383.1
LOC105374804	XR_007087045.1	n.-144_-143delGG		upstream_gene_variant
LOC105374804	XR_007087053.1	n.-144_-143delGG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.-45_-44delCC		upstream_gene_variant		1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000195 AC: 1 AN: 513352 Hom.: 0 AF XY: 0.00000362 AC XY: 1 AN XY: 276164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14120

American (AMR) AF: 0.00 AC: 0 AN: 29628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17330

East Asian (EAS) AF: 0.00 AC: 0 AN: 30606

South Asian (SAS) AF: 0.00 AC: 0 AN: 55340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2268

European-Non Finnish (NFE) AF: 0.00000331 AC: 1 AN: 302134

Other (OTH) AF: 0.00 AC: 0 AN: 28652

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

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: rs764473588; hg19: chr2-73612951;