rs374267052

Variant names:

• chrX-11114824-G-C
• rs374267052
• NM_005333.5:c.101-11G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005333.5(HCCS):​c.101-11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,204,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 83 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 0.00017 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00019 (0 hom. 78 hem.)
• Consequence: HCCS NM_005333.5 intron
• Scores: Splicing: ADA: 0.00004864
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.950
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• linear skin defects with multiple congenital anomalies 1

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• linear skin defects with multiple congenital anomalies

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-11114824-G-C is Benign according to our data. Variant chrX-11114824-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2659980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	NM_005333.5	MANE Select	c.101-11G>C		intron	N/A	NP_005324.3	P53701
	HCCS	NM_001122608.3		c.101-11G>C		intron	N/A	NP_001116080.1	P53701
	HCCS	NM_001171991.3		c.101-11G>C		intron	N/A	NP_001165462.1	P53701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	ENST00000380762.5	TSL:1 MANE Select	c.101-11G>C		intron	N/A	ENSP00000370139.4	P53701
	HCCS	ENST00000380763.7	TSL:1	c.101-11G>C		intron	N/A	ENSP00000370140.3	P53701
	HCCS	ENST00000321143.8	TSL:2	c.101-11G>C		intron	N/A	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes AF: 0.000170 AC: 19 AN: 111771 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000755

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 35 AN: 182903 AF XY: 0.000223

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.000938

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000193 AC: 211 AN: 1092406 Hom.: 0 Cov.: 29 AF XY: 0.000218 AC XY: 78 AN XY: 358054

African (AFR) AF: 0.0000380 AC: 1 AN: 26298

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.000826 AC: 16 AN: 19360

East Asian (EAS) AF: 0.00328 AC: 99 AN: 30183

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40355

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4023

European-Non Finnish (NFE) AF: 0.000109 AC: 91 AN: 837097

Other (OTH) AF: 0.0000654 AC: 3 AN: 45898

GnomAD4 genome AF: 0.000170 AC: 19 AN: 111824 Hom.: 0 Cov.: 24 AF XY: 0.000147 AC XY: 5 AN XY: 34008

African (AFR) AF: 0.00 AC: 0 AN: 30704

American (AMR) AF: 0.00 AC: 0 AN: 10570

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 2 AN: 2650

East Asian (EAS) AF: 0.00141 AC: 5 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53171

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.000155

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.3
DANN	Benign	0.75
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
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

Other links and lift over

dbSNP: rs374267052; hg19: chrX-11132944;