3-43690974-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016006.6(ABHD5):c.-19C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,568,598 control chromosomes in the GnomAD database, including 894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (56 hom., cov: 32)
  • Exomes 𝑓: 0.028 (838 hom.)
• Consequence: ABHD5 NM_016006.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.30

Genes affected

ABHD5 (HGNC:21396): (abhydrolase domain containing 5, lysophosphatidic acid acyltransferase) The protein encoded by this gene belongs to a large family of proteins defined by an alpha/beta hydrolase fold, and contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. It differs from other members of this subfamily in that its putative catalytic triad contains an asparagine instead of the serine residue. Mutations in this gene have been associated with Chanarin-Dorfman syndrome, a triglyceride storage disease with impaired long-chain fatty acid oxidation. [provided by RefSeq, Jul 2008]

ANO10 (HGNC:25519): (anoctamin 10) The transmembrane protein encoded by this gene belongs to the anoctamin family of calcium-activated chloride channels, also known as the transmembrane 16 family. The encoded protein contains eight transmembrane domains with cytosolic N- and C-termini. Defects in this gene may cause autosomal recessive spinocerebellar ataxia-10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-43690974-C-T is Benign according to our data. Variant chr3-43690974-C-T is described in ClinVar as [Benign]. Clinvar id is 345213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD5	NM_016006.6	c.-19C>T		5_prime_UTR_variant	1/7	ENST00000644371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD5	ENST00000644371.2	c.-19C>T		5_prime_UTR_variant	1/7		NM_016006.6	P1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3209 AN: 152000 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00785

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0268

Gnomad SAS AF: 0.0916

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0320 AC: 6336 AN: 197706 Hom.: 183 AF XY: 0.0363 AC XY: 4005 AN XY: 110294

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.0216

Gnomad SAS exome AF: 0.0943

Gnomad FIN exome AF: 0.00739

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0281 AC: 39762 AN: 1416490 Hom.: 838 Cov.: 31 AF XY: 0.0302 AC XY: 21256 AN XY: 704468

Gnomad4 AFR exome AF: 0.00667

Gnomad4 AMR exome AF: 0.0301

Gnomad4 ASJ exome AF: 0.0312

Gnomad4 EAS exome AF: 0.0300

Gnomad4 SAS exome AF: 0.0904

Gnomad4 FIN exome AF: 0.00746

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0307

GnomAD4 genome AF: 0.0211 AC: 3214 AN: 152108 Hom.: 56 Cov.: 32 AF XY: 0.0214 AC XY: 1593 AN XY: 74366

Gnomad4 AFR AF: 0.00799

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.0265

Gnomad4 SAS AF: 0.0917

Gnomad4 FIN AF: 0.00500

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0222 Hom.: 18

Bravo AF: 0.0202

Asia WGS AF: 0.0460 AC: 158 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Triglyceride storage disease with ichthyosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.28
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs117630969; hg19: chr3-43732466; COSMIC: COSV50006580; COSMIC: COSV50006580;