3-43702422-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016006.6(ABHD5):c.341G>T(p.Arg114Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0104 in 1,614,200 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (126 hom.)
• Consequence: ABHD5 NM_016006.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.10

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023979723).
• BP6: Variant 3-43702422-G-T is Benign according to our data. Variant chr3-43702422-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-43702422-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00722 (1100/152314) while in subpopulation NFE AF= 0.0124 (843/68032). AF 95% confidence interval is 0.0117. There are 5 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD5	NM_016006.6	c.341G>T	p.Arg114Leu	missense_variant	3/7	ENST00000644371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD5	ENST00000644371.2	c.341G>T	p.Arg114Leu	missense_variant	3/7		NM_016006.6	P1

Frequencies

GnomAD3 genomes AF: 0.00723 AC: 1100 AN: 152196 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00777 AC: 1953 AN: 251474 Hom.: 21 AF XY: 0.00807 AC XY: 1097 AN XY: 135912

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00719

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0107 AC: 15679 AN: 1461886 Hom.: 126 Cov.: 31 AF XY: 0.0106 AC XY: 7745 AN XY: 727242

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00744

Gnomad4 FIN exome AF: 0.00751

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00722 AC: 1100 AN: 152314 Hom.: 5 Cov.: 32 AF XY: 0.00667 AC XY: 497 AN XY: 74478

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00594

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.0105 Hom.: 17

Bravo AF: 0.00668

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0131 AC: 113

ExAC AF: 0.00829 AC: 1006

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABHD5: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Triglyceride storage disease with ichthyosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;D;.;D
MetaRNN	Benign	0.024	T;T;T;T;T
MetaSVM	Uncertain	0.071	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.4	D;.;D;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;D;.;.
Polyphen		1.0	.;D;.;.;.
Vest4		0.72
MVP		0.87
MPC		0.61
ClinPred		0.035	T
GERP RS		4.0
Varity_R		0.60
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148743497; hg19: chr3-43743914; COSMIC: COSV50006506; COSMIC: COSV50006506;