2-73385828-CCCT-C

Variant names:

• chr2-73385828-CCCT-C
• rs746980000
• NM_001378454.1:c.-27_-25delCTC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001378454.1(ALMS1):​c.-27_-25delCTC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 386,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALMS1 NM_001378454.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.312
• 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 0 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0286) population. However there is too low homozygotes in high coverage region: (expected more than 57, got 0).
• BP6: Variant 2-73385828-CCCT-C is Benign according to our data. Variant chr2-73385828-CCCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 337004.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.-27_-25delCTC		5_prime_UTR_variant	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_001378454.1	c.-40_-38delCCT		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.-27_-25delCTC		5_prime_UTR_variant	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1
ALMS1	ENST00000613296.6	c.-40_-38delCCT		upstream_gene_variant		1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151496 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0253 AC: 1773 AN: 69986 AF XY: 0.0245

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.0278

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.0337

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0242

GnomAD4 exome AF: 0.0245 AC: 9465 AN: 386836 Hom.: 0 AF XY: 0.0231 AC XY: 4815 AN XY: 208532

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

African (AFR) AF: 0.0313 AC: 349 AN: 11166

American (AMR) AF: 0.0244 AC: 654 AN: 26774

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 382 AN: 13550

East Asian (EAS) AF: 0.0270 AC: 614 AN: 22718

South Asian (SAS) AF: 0.0158 AC: 704 AN: 44586

European-Finnish (FIN) AF: 0.0256 AC: 610 AN: 23798

Middle Eastern (MID) AF: 0.0271 AC: 46 AN: 1698

European-Non Finnish (NFE) AF: 0.0251 AC: 5552 AN: 221604

Other (OTH) AF: 0.0265 AC: 554 AN: 20942

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000396 AC: 6 AN: 151596 Hom.: 0 Cov.: 32 AF XY: 0.0000675 AC XY: 5 AN XY: 74088

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67748

Other (OTH) AF: 0.00 AC: 0 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.002092), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0148 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alstrom syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.31
Mutation Taster		=259/41	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: rs746980000; hg19: chr2-73612956; COSMIC: COSV52511595; COSMIC: COSV52511595;