14-73478694-G-C

Variant summary

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

The NM_001220484.1(HEATR4):ā€‹c.2993C>Gā€‹(p.Pro998Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,820 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

HEATR4
NM_001220484.1 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.485
Variant links:
Genes affected
HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

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=0.046010613).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HEATR4NM_001220484.1 linkc.2993C>G p.Pro998Arg missense_variant 18/18 ENST00000553558.6 NP_001207413.1 Q86WZ0
HEATR4NM_203309.2 linkc.2993C>G p.Pro998Arg missense_variant 17/17 NP_976054.2 Q86WZ0
HEATR4XM_047431370.1 linkc.2993C>G p.Pro998Arg missense_variant 17/17 XP_047287326.1
HEATR4XM_047431371.1 linkc.1724C>G p.Pro575Arg missense_variant 15/15 XP_047287327.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HEATR4ENST00000553558.6 linkc.2993C>G p.Pro998Arg missense_variant 18/182 NM_001220484.1 ENSP00000450444.2 Q86WZ0
HEATR4ENST00000334988.2 linkc.2993C>G p.Pro998Arg missense_variant 17/171 ENSP00000335447.2 Q86WZ0
HEATR4ENST00000565094.1 linkn.174C>G non_coding_transcript_exon_variant 2/25
HEATR4ENST00000566478.1 linkn.200C>G non_coding_transcript_exon_variant 2/25

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
151960
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000967
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251442
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000867
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461860
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.0000894
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:
0.0000263
AC:
4
AN:
151960
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74226
show subpopulations
Gnomad4 AFR
AF:
0.0000967
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingAmbry GeneticsFeb 06, 2023The c.2993C>G (p.P998R) 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 2993, causing the proline (P) at amino acid position 998 to be replaced by an arginine (R). 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
0.092
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
5.7
DANN
Benign
0.93
DEOGEN2
Benign
0.0011
T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.35
.;T
M_CAP
Benign
0.0042
T
MetaRNN
Benign
0.046
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
0.090
N;N
REVEL
Benign
0.027
Sift
Uncertain
0.025
D;D
Sift4G
Uncertain
0.037
D;D
Polyphen
0.0010
B;B
Vest4
0.22
MVP
0.014
MPC
0.13
ClinPred
0.060
T
GERP RS
0.31
Varity_R
0.055
gMVP
0.051

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.

Other links and lift over

dbSNP: rs150958075; hg19: chr14-73945399; API