3-43691003-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016006.6(ABHD5):c.11A>C(p.Glu4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,561,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E4E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ABHD5 NM_016006.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.239

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008296251).
• BP6: Variant 3-43691003-A-C is Benign according to our data. Variant chr3-43691003-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 901881.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD5	NM_016006.6	c.11A>C	p.Glu4Ala	missense_variant	1/7	ENST00000644371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD5	ENST00000644371.2	c.11A>C	p.Glu4Ala	missense_variant	1/7		NM_016006.6	P1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 121 AN: 150820 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000266 AC: 52 AN: 195568 Hom.: 0 AF XY: 0.000238 AC XY: 26 AN XY: 109248

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000823

Gnomad SAS exome AF: 0.000152

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000146 AC: 206 AN: 1410090 Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 101 AN XY: 701274

Gnomad4 AFR exome AF: 0.00256

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.0000406

Gnomad4 EAS exome AF: 0.0000292

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000900

Gnomad4 OTH exome AF: 0.000293

GnomAD4 genome AF: 0.000802 AC: 121 AN: 150930 Hom.: 0 Cov.: 32 AF XY: 0.000760 AC XY: 56 AN XY: 73682

Gnomad4 AFR AF: 0.00275

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000591

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.000929

ESP6500AA AF: 0.000691 AC: 3

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000291 AC: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Triglyceride storage disease with ichthyosis Uncertain:1

Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	17
Dann	Benign	0.91
DEOGEN2	Benign	0.099	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.40	N
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.72	T
Polyphen		0.0060	B;.
Vest4		0.45
MVP		0.58
MPC		0.16
ClinPred		0.011	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.048
gMVP		0.41

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: rs138400599; hg19: chr3-43732495; COSMIC: COSV50006445; COSMIC: COSV50006445;