Genetic Variant NM_005333.5:c.522-860T>C (chrX-11120047-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005333.5(HCCS):c.522-860T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 323,350 control chromosomes in the GnomAD database, including 2 homozygotes. There are 183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., 71 hem., cov: 23)

Exomes 𝑓: 0.0015 ( 1 hom. 112 hem. )

Consequence

HCCS
NM_005333.5 intron

Scores

Splicing: ADA: 0.0002072

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.857

Publications

0 publications found

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:

ARHGAP6 (HGNC:676): (Rho GTPase activating protein 6) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of actin polymerization at the plasma membrane during several cellular processes. This protein is thought to have two independent functions, one as a GTPase-activating protein with specificity for RhoA, and another as a cytoskeletal protein that promotes actin remodeling. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ARHGAP6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant X-11120047-T-C is Benign according to our data. Variant chrX-11120047-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2659981.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 71 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005333.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HCCS	NM_005333.5	MANE Select	c.522-860T>C	intron	N/A	NP_005324.3	P53701
HCCS	NM_001122608.3		c.522-860T>C	intron	N/A	NP_001116080.1	P53701
HCCS	NM_001171991.3		c.522-860T>C	intron	N/A	NP_001165462.1	P53701

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HCCS	ENST00000380762.5	TSL:1 MANE Select	c.522-860T>C	intron	N/A	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7	TSL:1	c.522-860T>C	intron	N/A	ENSP00000370140.3	P53701
ARHGAP6	ENST00000657361.1		c.1733-2A>G	splice_acceptor intron	N/A	ENSP00000499351.1	B4DN07

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

184

AN:

112254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000324

Gnomad AMI

AF:

0.00146

Gnomad AMR

AF:

0.00188

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00736

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00197

GnomAD2 exomes

AF:

0.00114

AC:

AN:

83168

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000449

Gnomad AMR exome

AF:

0.000594

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00716

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00267

GnomAD4 exome

AF:

0.00152

AC:

320

AN:

211041

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

112

AN XY:

81069

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

6610

American (AMR)

AF:

0.000690

AC:

AN:

20299

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7719

East Asian (EAS)

AF:

0.00

AC:

AN:

6508

South Asian (SAS)

AF:

0.0000592

AC:

AN:

33780

European-Finnish (FIN)

AF:

0.00667

AC:

AN:

9302

Middle Eastern (MID)

AF:

0.00247

AC:

AN:

2021

European-Non Finnish (NFE)

AF:

0.00189

AC:

216

AN:

114514

Other (OTH)

AF:

0.00194

AC:

AN:

10288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00164

AC:

184

AN:

112309

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

AN XY:

34479

show subpopulations

African (AFR)

AF:

0.000323

AC:

AN:

30937

American (AMR)

AF:

0.00188

AC:

AN:

10657

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3583

South Asian (SAS)

AF:

0.00

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00736

AC:

AN:

6110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00197

AC:

105

AN:

53245

Other (OTH)

AF:

0.00195

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00115

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

-0.86

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over