NM_005333.5:c.55G>C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005333.5(HCCS):c.55G>C(p.Ala19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,208,387 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 5 hem. )

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.346893).

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5 link	c.55G>C	p.Ala19Pro	missense_variant	Exon 2 of 7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 link	c.55G>C	p.Ala19Pro	missense_variant	Exon 2 of 7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 link	c.55G>C	p.Ala19Pro	missense_variant	Exon 2 of 7		NP_001165462.1	P53701A0A024RBY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCCS	ENST00000380762.5 link	c.55G>C	p.Ala19Pro	missense_variant	Exon 2 of 7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 link	c.55G>C	p.Ala19Pro	missense_variant	Exon 2 of 7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 link	c.55G>C	p.Ala19Pro	missense_variant	Exon 2 of 7	2		ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112486

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34644

show subpopulations

Gnomad AFR

AF:

0.0000647

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183401

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67839

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1095901

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361291

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:

0.0000179

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112486

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34644

show subpopulations

Gnomad4 AFR

AF:

0.0000647

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 19 of the HCCS protein (p.Ala19Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HCCS-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

0.00088

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;T

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.40

.;.;T

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.8

L;L;L

PrimateAI

Benign

0.37

PROVEAN

Benign

0.090

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.075

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.57

P;P;P

Vest4

0.15

MutPred

0.14

Gain of glycosylation at A19 (P = 0.0078);Gain of glycosylation at A19 (P = 0.0078);Gain of glycosylation at A19 (P = 0.0078);

MVP

0.85

MPC

1.3

ClinPred

0.56

GERP RS

3.9

Varity_R

0.15

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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