rs1053926

Variant names:

• chr10-17594310-G-A
• rs1053926
• NM_014241.4:c.679C>T

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.679C>T​(p.His227Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.26 in 1,599,898 control chromosomes in the GnomAD database, including 57,144 homozygotes. 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (5091 hom., cov: 32)
  • Exomes 𝑓: 0.26 (52053 hom.)
• Consequence: HACD1 NM_014241.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.80
• Publications: 24 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 (MetaRNN=0.010225773).
• BP6: Variant 10-17594310-G-A is Benign according to our data. Variant chr10-17594310-G-A is described in ClinVar as Benign. ClinVar VariationId is 1295715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HACD1	NM_014241.4	c.679C>T	p.His227Tyr	missense_variant	Exon 6 of 7	ENST00000361271.8	NP_055056.3
HACD1	XM_005252641.5	c.571C>T	p.His191Tyr	missense_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.679C>T	p.His227Tyr	missense_variant	Exon 6 of 7	1	NM_014241.4	ENSP00000355308.3
HACD1	ENST00000471481.1	n.465C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3
HACD1	ENST00000498812.5	n.*68C>T		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000462868.1
HACD1	ENST00000498812.5	n.*68C>T		3_prime_UTR_variant	Exon 3 of 4	5		ENSP00000462868.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38212 AN: 151808 Hom.: 5084 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.0509

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.249

GnomAD2 exomes AF: 0.223 AC: 55039 AN: 246782 AF XY: 0.226

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.0568

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.280

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.261 AC: 377349 AN: 1447974 Hom.: 52053 Cov.: 32 AF XY: 0.259 AC XY: 186490 AN XY: 719956

African (AFR) AF: 0.248 AC: 8208 AN: 33084

American (AMR) AF: 0.126 AC: 5495 AN: 43472

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 8395 AN: 25630

East Asian (EAS) AF: 0.0378 AC: 1491 AN: 39488

South Asian (SAS) AF: 0.163 AC: 13706 AN: 83952

European-Finnish (FIN) AF: 0.241 AC: 12740 AN: 52904

Middle Eastern (MID) AF: 0.256 AC: 1460 AN: 5700

European-Non Finnish (NFE) AF: 0.281 AC: 310747 AN: 1104016

Other (OTH) AF: 0.253 AC: 15107 AN: 59728

GnomAD4 genome AF: 0.252 AC: 38230 AN: 151924 Hom.: 5091 Cov.: 32 AF XY: 0.245 AC XY: 18182 AN XY: 74238

African (AFR) AF: 0.251 AC: 10394 AN: 41410

American (AMR) AF: 0.191 AC: 2918 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3468

East Asian (EAS) AF: 0.0509 AC: 263 AN: 5170

South Asian (SAS) AF: 0.166 AC: 801 AN: 4814

European-Finnish (FIN) AF: 0.237 AC: 2489 AN: 10516

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.284 AC: 19272 AN: 67970

Other (OTH) AF: 0.247 AC: 519 AN: 2102

Alfa AF: 0.274 Hom.: 11347

Bravo AF: 0.248

TwinsUK AF: 0.283 AC: 1050

ALSPAC AF: 0.288 AC: 1111

ESP6500AA AF: 0.254 AC: 1118

ESP6500EA AF: 0.280 AC: 2405

ExAC AF: 0.231 AC: 28092

Asia WGS AF: 0.120 AC: 418 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 30, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.3
DANN	Benign	0.33
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.3	N
PhyloP100		3.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.29
ClinPred		0.0029	T
GERP RS		5.7
Varity_R		0.095
gMVP		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1053926; hg19: chr10-17636309; COSMIC: COSV63517260; COSMIC: COSV63517260;