rs2357285

Variant names:

• chr10-17590563-C-T
• rs2357285
• NM_014241.4:c.785-117G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014241.4(HACD1):​c.785-117G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 637,922 control chromosomes in the GnomAD database, including 879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (155 hom., cov: 32)
  • Exomes 𝑓: 0.048 (724 hom.)
• Consequence: HACD1 NM_014241.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.58
• Publications: 2 publications found

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]

HACD1 Gene-Disease associations (from GenCC):

• congenital myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 11

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-17590563-C-T is Benign according to our data. Variant chr10-17590563-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HACD1	NM_014241.4	c.785-117G>A		intron_variant	Intron 6 of 6	ENST00000361271.8	NP_055056.3
HACD1	XM_005252641.5	c.677-117G>A		intron_variant	Intron 4 of 4		XP_005252698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HACD1	ENST00000361271.8	c.785-117G>A		intron_variant	Intron 6 of 6	1	NM_014241.4	ENSP00000355308.3
HACD1	ENST00000498812.5	n.*174-117G>A		intron_variant	Intron 3 of 3	5		ENSP00000462868.1

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5880 AN: 152100 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0616

Gnomad OTH AF: 0.0297

GnomAD4 exome AF: 0.0477 AC: 23157 AN: 485704 Hom.: 724 AF XY: 0.0470 AC XY: 12062 AN XY: 256616

African (AFR) AF: 0.00808 AC: 98 AN: 12122

American (AMR) AF: 0.0150 AC: 209 AN: 13898

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 480 AN: 12496

East Asian (EAS) AF: 0.00 AC: 0 AN: 27822

South Asian (SAS) AF: 0.0148 AC: 554 AN: 37356

European-Finnish (FIN) AF: 0.0515 AC: 1522 AN: 29562

Middle Eastern (MID) AF: 0.00612 AC: 13 AN: 2124

European-Non Finnish (NFE) AF: 0.0592 AC: 19206 AN: 324476

Other (OTH) AF: 0.0416 AC: 1075 AN: 25848

GnomAD4 genome AF: 0.0387 AC: 5885 AN: 152218 Hom.: 155 Cov.: 32 AF XY: 0.0369 AC XY: 2743 AN XY: 74408

African (AFR) AF: 0.0101 AC: 418 AN: 41548

American (AMR) AF: 0.0275 AC: 420 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4812

European-Finnish (FIN) AF: 0.0464 AC: 491 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0617 AC: 4193 AN: 68010

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0458 Hom.: 381

Bravo AF: 0.0353

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.0
DANN	Benign	0.68
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2357285; hg19: chr10-17632562;