Variant 14-73478819-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001220484.1(HEATR4):c.2868T>A(p.Asn956Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,609,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

HEATR4
NM_001220484.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.41

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 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=0.1911062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEATR4	NM_001220484.1 linkuse as main transcript	c.2868T>A	p.Asn956Lys	missense_variant	18/18	ENST00000553558.6	NP_001207413.1	Q86WZ0
HEATR4	NM_203309.2 linkuse as main transcript	c.2868T>A	p.Asn956Lys	missense_variant	17/17		NP_976054.2	Q86WZ0
HEATR4	XM_047431370.1 linkuse as main transcript	c.2868T>A	p.Asn956Lys	missense_variant	17/17		XP_047287326.1
HEATR4	XM_047431371.1 linkuse as main transcript	c.1599T>A	p.Asn533Lys	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.2868T>A	p.Asn956Lys	missense_variant	18/18	2	NM_001220484.1	ENSP00000450444.2	Q86WZ0
HEATR4	ENST00000334988.2 linkuse as main transcript	c.2868T>A	p.Asn956Lys	missense_variant	17/17	1		ENSP00000335447.2	Q86WZ0
HEATR4	ENST00000565094.1 linkuse as main transcript	n.49T>A		non_coding_transcript_exon_variant	2/2	5
HEATR4	ENST00000566478.1 linkuse as main transcript	n.75T>A		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

246144

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133562

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000134

AC:

196

AN:

1457482

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

724908

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.0000229

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:

0.000173

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

May 04, 2023

The c.2868T>A (p.N956K) alteration is located in exon 18 (coding exon 16) of the HEATR4 gene. This alteration results from a T to A substitution at nucleotide position 2868, causing the asparagine (N) at amino acid position 956 to be replaced by a lysine (K). 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

0.28

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0012

T;T

Eigen

Benign

0.057

Eigen_PC

Benign

0.093

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.38

.;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.77

N;N

REVEL

Benign

0.060

Sift

Uncertain

0.019

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.91

P;P

Vest4

0.30

MutPred

0.13

Gain of methylation at N956 (P = 0.0087);Gain of methylation at N956 (P = 0.0087);

MVP

0.27

MPC

0.33

ClinPred

0.89

GERP RS

3.2

Varity_R

0.098

gMVP

0.31

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