Genetic Variant HEATR4:p.Asp996Tyr (chr14-73478701-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001220484.1(HEATR4):c.2986G>T(p.Asp996Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,198 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HEATR4
NM_001220484.1 missense

Scores

Clinical Significance

Not reported in ClinVar

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 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=0.16886047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR4	NM_001220484.1 link	c.2986G>T	p.Asp996Tyr	missense_variant	Exon 18 of 18	ENST00000553558.6	NP_001207413.1	Q86WZ0
HEATR4	NM_203309.2 link	c.2986G>T	p.Asp996Tyr	missense_variant	Exon 17 of 17		NP_976054.2	Q86WZ0
HEATR4	XM_047431370.1 link	c.2986G>T	p.Asp996Tyr	missense_variant	Exon 17 of 17		XP_047287326.1
HEATR4	XM_047431371.1 link	c.1717G>T	p.Asp573Tyr	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>T	p.Asp996Tyr	missense_variant	Exon 18 of 18	2	NM_001220484.1	ENSP00000450444.2		Q86WZ0

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151198

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:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251412

Hom.:

AF XY:

0.00

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:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73704

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.6

DANN

Benign

0.96

DEOGEN2

Benign

0.0014

T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

0.77

P;P

Vest4

0.49

MutPred

0.36

Loss of disorder (P = 0.0412);Loss of disorder (P = 0.0412);

MVP

0.030

MPC

0.38

ClinPred

0.27

GERP RS

0.77

Varity_R

0.059

gMVP

0.28

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over