Genetic Variant NM_005333.5:c.178G>A (chrX-11114912-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_005333.5(HCCS):c.178G>A(p.Ala60Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,090,777 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.61

Variant links:

Genes affected

HCCS (HGNC:4837): (holocytochrome c synthase) The protein encoded by this gene is an enzyme that covalently links a heme group to the apoprotein of cytochrome c. Defects in this gene are a cause of microphthalmia syndromic type 7 (MCOPS7). Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jan 2010]

HCCS links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5 link	c.178G>A	p.Ala60Thr	missense_variant	Exon 3 of 7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 link	c.178G>A	p.Ala60Thr	missense_variant	Exon 3 of 7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 link	c.178G>A	p.Ala60Thr	missense_variant	Exon 3 of 7		NP_001165462.1	P53701A0A024RBY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCCS	ENST00000380762.5 link	c.178G>A	p.Ala60Thr	missense_variant	Exon 3 of 7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 link	c.178G>A	p.Ala60Thr	missense_variant	Exon 3 of 7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 link	c.178G>A	p.Ala60Thr	missense_variant	Exon 3 of 7	2		ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183458

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000721

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000550

AC:

AN:

1090777

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

356391

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000479

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.178G>A (p.A60T) alteration is located in exon 3 (coding exon 2) of the HCCS gene. This alteration results from a G to A substitution at nucleotide position 178, causing the alanine (A) at amino acid position 60 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

0.28

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;T;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

.;.;D

M_CAP

Pathogenic

0.70

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Uncertain

0.020

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.14

N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.56

MutPred

0.41

Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);

MVP

0.89

MPC

0.46

ClinPred

0.54

GERP RS

5.1

Varity_R

0.31

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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