rs104893675

Variant names:

• chr3-43699326-C-G
• rs104893675
• NM_016006.6:c.98C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016006.6(ABHD5):​c.98C>G​(p.Ser33*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABHD5 NM_016006.6 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.00700
• Publications: 4 publications found

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]

ABHD5 Gene-Disease associations (from GenCC):

• Dorfman-Chanarin disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-43699326-C-G is Pathogenic according to our data. Variant chr3-43699326-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5348.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016006.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD5	NM_016006.6	MANE Select	c.98C>G	p.Ser33*	stop_gained	Exon 2 of 7	NP_057090.2
	ABHD5	NM_001365649.1		c.-26C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001352578.1
	ABHD5	NM_001355186.2		c.98C>G	p.Ser33*	stop_gained	Exon 2 of 8	NP_001342115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD5	ENST00000644371.2	MANE Select	c.98C>G	p.Ser33*	stop_gained	Exon 2 of 7	ENSP00000495778.1
	ABHD5	ENST00000458276.7	TSL:1	c.98C>G	p.Ser33*	stop_gained	Exon 2 of 6	ENSP00000390849.3
	ABHD5	ENST00000454293.2	TSL:3	c.-26C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000412014.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Triglyceride storage disease with ichthyosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Benign	0.89
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.14	N
PhyloP100		-0.0070
Vest4		0.76
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=20/180	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.040		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: rs104893675; hg19: chr3-43740818;