19-3880660-A-G

Variant names:

• chr19-3880660-A-G
• rs140876148
• ENST00000598136.5:c.-140-250A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000598136.5(ATCAY):​c.-140-250A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 152,058 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATCAY ENST00000598136.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.363
• Publications: 0 publications found

Genes affected

ATCAY (HGNC:779): (ATCAY kinesin light chain interacting caytaxin) This gene encodes a neuron-restricted protein that contains a CRAL-TRIO motif common to proteins that bind small lipophilic molecules. Mutations in this gene are associated with cerebellar ataxia, Cayman type. [provided by RefSeq, Jul 2008]

ATCAY Gene-Disease associations (from GenCC):

• cerebellar ataxia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Cayman type cerebellar ataxia

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-3880660-A-G is Benign according to our data. Variant chr19-3880660-A-G is described in ClinVar as [Benign]. Clinvar id is 328981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00376 (572/152058) while in subpopulation EAS AF = 0.0324 (166/5128). AF 95% confidence interval is 0.0284. There are 9 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATCAY	NM_033064.5	c.-390A>G		upstream_gene_variant		ENST00000450849.7	NP_149053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATCAY	ENST00000598136.5	c.-140-250A>G		intron_variant	Intron 1 of 4	4		ENSP00000471731.1
ATCAY	ENST00000450849.7	c.-390A>G		upstream_gene_variant		1	NM_033064.5	ENSP00000390941.1
ATCAY	ENST00000595916.5	n.-25A>G		upstream_gene_variant		4
ATCAY	ENST00000597739.1	n.-390A>G		upstream_gene_variant		2		ENSP00000472263.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 571 AN: 151940 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00384

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 78 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 52

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152058 Hom.: 9 Cov.: 31 AF XY: 0.00397 AC XY: 295 AN XY: 74326

African (AFR) AF: 0.000964 AC: 40 AN: 41502

American (AMR) AF: 0.00852 AC: 130 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0324 AC: 166 AN: 5128

South Asian (SAS) AF: 0.0113 AC: 54 AN: 4798

European-Finnish (FIN) AF: 0.00321 AC: 34 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 67982

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00434

Asia WGS AF: 0.0180 AC: 64 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cayman type cerebellar ataxia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.1
DANN	Benign	0.78
PhyloP100		0.36
PromoterAI		0.0030	Neutral
Mutation Taster		=300/0	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: rs140876148; hg19: chr19-3880658;