Variant chr14-73478641-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001220484.1(HEATR4):c.3046T>C(p.Ser1016Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HEATR4
NM_001220484.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.50

Variant links:

Genes affected

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

HEATR4 links:

HEATR4 (HGNC:):

HEATR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04956165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEATR4	NM_001220484.1 linkuse as main transcript	c.3046T>C	p.Ser1016Pro	missense_variant	18/18	ENST00000553558.6	NP_001207413.1	Q86WZ0
HEATR4	NM_203309.2 linkuse as main transcript	c.3046T>C	p.Ser1016Pro	missense_variant	17/17		NP_976054.2	Q86WZ0
HEATR4	XM_047431370.1 linkuse as main transcript	c.3046T>C	p.Ser1016Pro	missense_variant	17/17		XP_047287326.1
HEATR4	XM_047431371.1 linkuse as main transcript	c.1777T>C	p.Ser593Pro	missense_variant	15/15		XP_047287327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HEATR4	ENST00000553558.6 linkuse as main transcript	c.3046T>C	p.Ser1016Pro	missense_variant	18/18	2	NM_001220484.1	ENSP00000450444.2	Q86WZ0
HEATR4	ENST00000334988.2 linkuse as main transcript	c.3046T>C	p.Ser1016Pro	missense_variant	17/17	1		ENSP00000335447.2	Q86WZ0
HEATR4	ENST00000565094.1 linkuse as main transcript	n.227T>C		non_coding_transcript_exon_variant	2/2	5
HEATR4	ENST00000566478.1 linkuse as main transcript	n.253T>C		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.3046T>C (p.S1016P) alteration is located in exon 18 (coding exon 16) of the HEATR4 gene. This alteration results from a T to C substitution at nucleotide position 3046, causing the serine (S) at amino acid position 1016 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

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.13

DANN

Benign

0.87

DEOGEN2

Benign

0.0027

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.21

.;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.045

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.26

T;T

Polyphen

0.0010

B;B

Vest4

0.20

MutPred

0.19

Loss of phosphorylation at S1016 (P = 0.0287);Loss of phosphorylation at S1016 (P = 0.0287);

MVP

0.014

MPC

0.14

ClinPred

0.24

GERP RS

-8.4

Varity_R

0.17

gMVP

0.012

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over