19-3905423-T-C

Variant names:

• chr19-3905423-T-C
• rs73919387
• NM_033064.5:c.137-11T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033064.5(ATCAY):​c.137-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,584,606 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (75 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (78 hom.)
• Consequence: ATCAY NM_033064.5 intron
• Scores: Splicing: ADA: 0.0001163
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.371
• Publications: 2 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=-0.83).
• BP6: Variant 19-3905423-T-C is Benign according to our data. Variant chr19-3905423-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 329117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATCAY	NM_033064.5	c.137-11T>C		intron_variant	Intron 3 of 12	ENST00000450849.7	NP_149053.1
ATCAY	XM_047439578.1	c.-251-11T>C		intron_variant	Intron 2 of 11		XP_047295534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATCAY	ENST00000450849.7	c.137-11T>C		intron_variant	Intron 3 of 12	1	NM_033064.5	ENSP00000390941.1
ATCAY	ENST00000600960.1	c.137-11T>C		intron_variant	Intron 2 of 12	5		ENSP00000470842.1
ATCAY	ENST00000598136.5	c.137-11T>C		intron_variant	Intron 4 of 4	4		ENSP00000471731.1
ATCAY	ENST00000597739.1	n.208-11T>C		intron_variant	Intron 4 of 13	2		ENSP00000472263.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2872 AN: 152080 Hom.: 74 Cov.: 31

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00476 AC: 1027 AN: 215718 AF XY: 0.00354

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00178 AC: 2544 AN: 1432408 Hom.: 78 Cov.: 31 AF XY: 0.00151 AC XY: 1072 AN XY: 709278

African (AFR) AF: 0.0650 AC: 2118 AN: 32584

American (AMR) AF: 0.00386 AC: 151 AN: 39140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 38860

South Asian (SAS) AF: 0.000120 AC: 10 AN: 83146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52486

Middle Eastern (MID) AF: 0.000705 AC: 4 AN: 5670

European-Non Finnish (NFE) AF: 0.0000265 AC: 29 AN: 1096058

Other (OTH) AF: 0.00391 AC: 232 AN: 59262

GnomAD4 genome AF: 0.0189 AC: 2876 AN: 152198 Hom.: 75 Cov.: 31 AF XY: 0.0185 AC XY: 1380 AN XY: 74416

African (AFR) AF: 0.0640 AC: 2658 AN: 41538

American (AMR) AF: 0.0104 AC: 158 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68004

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.00932 Hom.: 4

Bravo AF: 0.0218

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cayman type cerebellar ataxia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.83
CADD	Benign	0.58
DANN	Benign	0.41
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.026
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: rs73919387; hg19: chr19-3905421;