10-17590394-A-C

Variant names:

• chr10-17590394-A-C
• rs541937721
• NM_014241.4:c.837T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014241.4(HACD1):​c.837T>G​(p.His279Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H279R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HACD1 NM_014241.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16901323).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014241.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACD1	NM_014241.4	MANE Select	c.837T>G	p.His279Gln	missense	Exon 7 of 7	NP_055056.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACD1	ENST00000361271.8	TSL:1 MANE Select	c.837T>G	p.His279Gln	missense	Exon 7 of 7	ENSP00000355308.3	B0YJ81-1
	HACD1	ENST00000957763.1		c.927T>G	p.His309Gln	missense	Exon 8 of 8	ENSP00000627822.1
	HACD1	ENST00000957762.1		c.885T>G	p.His295Gln	missense	Exon 8 of 8	ENSP00000627821.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452476 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723032

African (AFR) AF: 0.00 AC: 0 AN: 33078

American (AMR) AF: 0.00 AC: 0 AN: 44008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105572

Other (OTH) AF: 0.00 AC: 0 AN: 60050

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.094
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.17
Sift	Benign	0.095	T
Sift4G	Benign	0.10	T
Polyphen		0.0060	B
Vest4		0.41
MutPred		0.50		Loss of catalytic residue at L278 (P = 0.1455)
MVP		0.14
MPC		0.77
ClinPred		0.90	D
GERP RS		-4.0
Varity_R		0.36
gMVP		0.60
Mutation Taster		=23/77	disease causing

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: rs541937721; hg19: chr10-17632393;