rs1053926

Positions:

• chr10-17594310-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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:2
• Conservation: PhyloP100: 3.80

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 Benign. Variant got -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 id 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/exons	MANE	UniProt
HACD1	NM_014241.4	c.679C>T	p.His227Tyr	missense_variant	6/7	ENST00000361271.8
HACD1	XM_005252641.5	c.571C>T	p.His191Tyr	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HACD1	ENST00000361271.8	c.679C>T	p.His227Tyr	missense_variant	6/7	1	NM_014241.4	P1
HACD1	ENST00000471481.1	n.465C>T		non_coding_transcript_exon_variant	3/3	3
HACD1	ENST00000498812.5	c.*68C>T		3_prime_UTR_variant, NMD_transcript_variant	3/4	5

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

GnomAD3 exomes AF: 0.223 AC: 55039 AN: 246782 Hom.: 7080 AF XY: 0.226 AC XY: 30175 AN XY: 133604

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 SAS exome AF: 0.162

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

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.0378

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.281

Gnomad4 OTH exome AF: 0.253

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

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.0509

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.247

Alfa AF: 0.277 Hom.: 8283

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	- -

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1053926; hg19: chr10-17636309; COSMIC: COSV63517260; COSMIC: COSV63517260;