3-43691004-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016006.6(ABHD5):c.12G>A(p.Glu4=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,569,968 control chromosomes in the GnomAD database, including 897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (60 hom., cov: 32)
  • Exomes 𝑓: 0.028 (837 hom.)
• Consequence: ABHD5 NM_016006.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.73

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 3-43691004-G-A is Benign according to our data. Variant chr3-43691004-G-A is described in ClinVar as [Benign]. Clinvar id is 345214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-43691004-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD5	NM_016006.6	c.12G>A	p.Glu4=	synonymous_variant	1/7	ENST00000644371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD5	ENST00000644371.2	c.12G>A	p.Glu4=	synonymous_variant	1/7		NM_016006.6	P1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3420 AN: 151932 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0919

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0324 AC: 6431 AN: 198706 Hom.: 188 AF XY: 0.0366 AC XY: 4054 AN XY: 110884

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0288

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.0219

Gnomad SAS exome AF: 0.0951

Gnomad FIN exome AF: 0.00749

Gnomad NFE exome AF: 0.0240

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0282 AC: 39971 AN: 1417930 Hom.: 837 Cov.: 31 AF XY: 0.0303 AC XY: 21360 AN XY: 705312

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0304

Gnomad4 ASJ exome AF: 0.0312

Gnomad4 EAS exome AF: 0.0301

Gnomad4 SAS exome AF: 0.0903

Gnomad4 FIN exome AF: 0.00750

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0313

GnomAD4 genome AF: 0.0226 AC: 3429 AN: 152038 Hom.: 60 Cov.: 32 AF XY: 0.0226 AC XY: 1676 AN XY: 74316

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.0266

Gnomad4 SAS AF: 0.0918

Gnomad4 FIN AF: 0.00500

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0236 Hom.: 20

Bravo AF: 0.0218

Asia WGS AF: 0.0470 AC: 161 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs141365045; hg19: chr3-43732496; COSMIC: COSV50006583; COSMIC: COSV50006583;