Variant 14-73478701-C-T 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.2986G>A(p.Asp996Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,836 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: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HEATR4
NM_001220484.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.196

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:

ENSG00000251393 (HGNC:):

ENSG00000251393 links:

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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=0.050414026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR4	NM_001220484.1 link	c.2986G>A	p.Asp996Asn	missense_variant	Exon 18 of 18	ENST00000553558.6	NP_001207413.1	Q86WZ0
HEATR4	NM_203309.2 link	c.2986G>A	p.Asp996Asn	missense_variant	Exon 17 of 17		NP_976054.2	Q86WZ0
HEATR4	XM_047431370.1 link	c.2986G>A	p.Asp996Asn	missense_variant	Exon 17 of 17		XP_047287326.1
HEATR4	XM_047431371.1 link	c.1717G>A	p.Asp573Asn	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 link	c.2986G>A	p.Asp996Asn	missense_variant	Exon 18 of 18	2	NM_001220484.1	ENSP00000450444.2		Q86WZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251412

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727230

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000278

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2986G>A (p.D996N) alteration is located in exon 18 (coding exon 16) of the HEATR4 gene. This alteration results from a G to A substitution at nucleotide position 2986, causing the aspartic acid (D) at amino acid position 996 to be replaced by an asparagine (N). 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

0.090

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.2

DANN

Benign

0.89

DEOGEN2

Benign

0.00054

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.12

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.0080

Sift

Benign

0.23

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0070

B;B

Vest4

0.14

MutPred

0.36

Gain of MoRF binding (P = 0.0818);Gain of MoRF binding (P = 0.0818);

MVP

0.014

MPC

0.11

ClinPred

0.031

GERP RS

0.77

Varity_R

0.036

gMVP

0.10

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