chr2-73385828-CCCTCCT-C

Variant names:

• chr2-73385828-CCCTCCT-C
• rs746980000
• NM_001378454.1:c.-30_-25delCTCCTC

Variant summary

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

The NM_001378454.1(ALMS1):​c.-30_-25delCTCCTC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000039 in 513,252 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: 0.0000039 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• 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_001378454.1	c.-30_-25delCTCCTC		5_prime_UTR_variant	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_001378454.1	c.-40_-35delCCTCCT		upstream_gene_variant		ENST00000613296.6	NP_001365383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.-30_-25delCTCCTC		5_prime_UTR_variant	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1
ALMS1	ENST00000613296.6	c.-40_-35delCCTCCT		upstream_gene_variant		1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000390 AC: 2 AN: 513252 Hom.: 0 AF XY: 0.00000362 AC XY: 1 AN XY: 276396

⚠️ 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: 14354

American (AMR) AF: 0.00 AC: 0 AN: 32282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17778

East Asian (EAS) AF: 0.00 AC: 0 AN: 30038

South Asian (SAS) AF: 0.00 AC: 0 AN: 56228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2272

European-Non Finnish (NFE) AF: 0.00000669 AC: 2 AN: 298980

Other (OTH) AF: 0.00 AC: 0 AN: 28460

⚠️ 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		1.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746980000; hg19: chr2-73612956;