Variant chr5-176388844-C-A 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_138820.4(HIGD2A):c.25C>A(p.Pro9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HIGD2A
NM_138820.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.41

Variant links:

Genes affected

HIGD2A (HGNC:28311): (HIG1 hypoxia inducible domain family member 2A) The protein encoded by this gene is a subunit of the cytochrome c oxidase complex (complex IV), which is the terminal enzyme in the mitochondrial respiratory chain. The encoded protein is an inner mitochondrial membrane protein and is a functional ortholog of the yeast respiratory supercomplex factor 1 (Rcf1). In mouse, the orthologous protein enhances cell survival under conditions of hypoxia. [provided by RefSeq, Sep 2016]

HIGD2A links:

NOP16 (HGNC:26934): (NOP16 nucleolar protein) This gene encodes a protein that is localized to the nucleolus. Expression of this gene is induced by estrogens and Myc protein and is a marker of poor patient survival in breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

NOP16 links:

ARL10 (HGNC:22042): (ADP ribosylation factor like GTPase 10) Predicted to enable GTP binding activity and GTPase activity. [provided by Alliance of Genome Resources, Apr 2022]

ARL10 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=0.18232736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HIGD2A	NM_138820.4 linkuse as main transcript	c.25C>A	p.Pro9Thr	missense_variant	1/2	ENST00000274787.3
ARL10	XM_011534529.4 linkuse as main transcript	c.561+19862C>A		intron_variant
ARL10	XM_011534530.4 linkuse as main transcript	c.561+19862C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIGD2A	ENST00000274787.3 linkuse as main transcript	c.25C>A	p.Pro9Thr	missense_variant	1/2	1	NM_138820.4	P1
NOP16	ENST00000618911.4 linkuse as main transcript	c.-305G>T		5_prime_UTR_variant	1/5	1			Q9Y3C1-3
ARL10	ENST00000514533.1 linkuse as main transcript	c.134-12897C>A		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250970

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

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:

0.00000137

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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

Cov.:

Bravo

AF:

0.00000378

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

Apr 22, 2022

The c.25C>A (p.P9T) alteration is located in exon 1 (coding exon 1) of the HIGD2A gene. This alteration results from a C to A substitution at nucleotide position 25, causing the proline (P) at amino acid position 9 to be replaced by a threonine (T). 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

0.079

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.72

M_CAP

Benign

0.072

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

0.67

N;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

REVEL

Benign

0.17

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.012

Polyphen

0.015

Vest4

0.50

MutPred

0.36

Gain of glycosylation at P9 (P = 0.0033);

MVP

0.092

MPC

1.7

ClinPred

0.83

GERP RS

4.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.12

gMVP

0.81

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