14-73498212-C-G

Variant names:

• chr14-73498212-C-G
• NM_001220484.1:c.2489G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001220484.1(HEATR4):​c.2489G>C​(p.Arg830Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEATR4 NM_001220484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.751

Genes affected

HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

ACOT1 (HGNC:33128): (acyl-CoA thioesterase 1) Enables acyl-CoA hydrolase activity. Involved in acyl-CoA metabolic process; long-chain fatty acid metabolic process; and very long-chain fatty acid metabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR4	NM_001220484.1	c.2489G>C	p.Arg830Pro	missense_variant	Exon 14 of 18	ENST00000553558.6	NP_001207413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEATR4	ENST00000553558.6	c.2489G>C	p.Arg830Pro	missense_variant	Exon 14 of 18	2	NM_001220484.1	ENSP00000450444.2
HEATR4	ENST00000334988.2	c.2489G>C	p.Arg830Pro	missense_variant	Exon 13 of 17	1		ENSP00000335447.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2489G>C (p.R830P) alteration is located in exon 14 (coding exon 12) of the HEATR4 gene. This alteration results from a G to C substitution at nucleotide position 2489, causing the arginine (R) at amino acid position 830 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.63	.;T
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.97	D;D
Vest4		0.67
MutPred		0.55		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.36
MPC		0.36
ClinPred		0.69	D
GERP RS		-1.4
Varity_R		0.46
gMVP		0.61

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-73964916;