14-73493112-A-G

Variant names:

• chr14-73493112-A-G
• NM_001220484.1:c.2798T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001220484.1(HEATR4):​c.2798T>C​(p.Leu933Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: HEATR4 NM_001220484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.569

Genes affected

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

RIOX1 (HGNC:20968): (ribosomal oxygenase 1) Predicted to enable histone H3-methyl-lysine-36 demethylase activity; histone H3-methyl-lysine-4 demethylase activity; and iron ion binding activity. Predicted to be involved in histone lysine demethylation; negative regulation of osteoblast differentiation; and negative regulation of transcription, DNA-templated. Located in nucleolus. [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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06980693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR4	NM_001220484.1	c.2798T>C	p.Leu933Pro	missense_variant	Exon 17 of 18	ENST00000553558.6	NP_001207413.1
RIOX1	NM_024644.5	c.*169A>G		3_prime_UTR_variant	Exon 1 of 1	ENST00000304061.8	NP_078920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEATR4	ENST00000553558.6	c.2798T>C	p.Leu933Pro	missense_variant	Exon 17 of 18	2	NM_001220484.1	ENSP00000450444.2
HEATR4	ENST00000334988.2	c.2798T>C	p.Leu933Pro	missense_variant	Exon 16 of 17	1		ENSP00000335447.2
RIOX1	ENST00000304061.8	c.*169A>G		3_prime_UTR_variant	Exon 1 of 1	6	NM_024644.5	ENSP00000477507.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2798T>C (p.L933P) alteration is located in exon 17 (coding exon 15) of the HEATR4 gene. This alteration results from a T to C substitution at nucleotide position 2798, causing the leucine (L) at amino acid position 933 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	0.075
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.26	.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.042
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.030	B;B
Vest4		0.15
MutPred		0.31		Gain of disorder (P = 0.0315);Gain of disorder (P = 0.0315);
MVP		0.23
MPC		0.18
ClinPred		0.15	T
GERP RS		3.3
Varity_R		0.18
gMVP		0.091

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr14-73959816; COSMIC: COSV100407980; COSMIC: COSV100407980;