10-17594241-AATAGT-A

Variant names:

• chr10-17594241-AATAGT-A
• rs1435802242
• NM_014241.4:c.743_747delACTAT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_014241.4(HACD1):​c.743_747delACTAT​(p.Tyr248LeufsTer39) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000657 in 152,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: HACD1 NM_014241.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.24

Genes affected

HACD1 (HGNC:9639): (3-hydroxyacyl-CoA dehydratase 1) The protein encoded by this gene contains a characteristic catalytic motif of the protein tyrosine phosphatases (PTPs) family. The PTP motif of this protein has the highly conserved arginine residue replaced by a proline residue; thus it may represent a distinct class of PTPs. Members of the PTP family are known to be signaling molecules that regulate a variety of cellular processes. This gene was preferentially expressed in both adult and fetal heart. A much lower expression level was detected in skeletal and smooth muscle tissues, and no expression was observed in other tissues. The tissue specific expression in the developing and adult heart suggests a role in regulating cardiac development and differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.143 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-17594241-AATAGT-A is Pathogenic according to our data. Variant chr10-17594241-AATAGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 1452988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HACD1	NM_014241.4	c.743_747delACTAT	p.Tyr248LeufsTer39	frameshift_variant	Exon 6 of 7	ENST00000361271.8	NP_055056.3
HACD1	XM_005252641.5	c.635_639delACTAT	p.Tyr212LeufsTer39	frameshift_variant	Exon 4 of 5		XP_005252698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HACD1	ENST00000361271.8	c.743_747delACTAT	p.Tyr248LeufsTer39	frameshift_variant	Exon 6 of 7	1	NM_014241.4	ENSP00000355308.3
HACD1	ENST00000471481.1	n.529_533delACTAT		non_coding_transcript_exon_variant	Exon 3 of 3	3
HACD1	ENST00000498812.5	n.*132_*136delACTAT		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000462868.1
HACD1	ENST00000498812.5	n.*132_*136delACTAT		3_prime_UTR_variant	Exon 3 of 4	5		ENSP00000462868.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr248Leufs*39) in the HACD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the HACD1 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HACD1 protein in which other variant(s) (p.Tyr248*) have been determined to be pathogenic (PMID: 23933735). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1452988). This variant has not been reported in the literature in individuals affected with HACD1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1435802242; hg19: chr10-17636240;