14-73478746-G-C

Variant names:

• chr14-73478746-G-C
• NM_001220484.1:c.2941C>G

Variant summary

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

The NM_001220484.1(HEATR4):​c.2941C>G​(p.Arg981Gly) 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: 31)
• Consequence: HEATR4 NM_001220484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

Genes affected

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

ENSG00000251393 (HGNC:):

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.2941C>G	p.Arg981Gly	missense_variant	Exon 18 of 18	ENST00000553558.6	NP_001207413.1
HEATR4	NM_203309.2	c.2941C>G	p.Arg981Gly	missense_variant	Exon 17 of 17		NP_976054.2
HEATR4	XM_047431370.1	c.2941C>G	p.Arg981Gly	missense_variant	Exon 17 of 17		XP_047287326.1
HEATR4	XM_047431371.1	c.1672C>G	p.Arg558Gly	missense_variant	Exon 15 of 15		XP_047287327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEATR4	ENST00000553558.6	c.2941C>G	p.Arg981Gly	missense_variant	Exon 18 of 18	2	NM_001220484.1	ENSP00000450444.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2941C>G (p.R981G) alteration is located in exon 18 (coding exon 16) of the HEATR4 gene. This alteration results from a C to G substitution at nucleotide position 2941, causing the arginine (R) at amino acid position 981 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0069	T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.96	D;D
Vest4		0.59
MutPred		0.34		Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);
MVP		0.12
MPC		0.37
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.10
gMVP		0.19

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: chr14-73945451;