X-11114841-C-T

Variant names:

• chrX-11114841-C-T
• rs1178817470
• NM_005333.5:c.107C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_005333.5(HCCS):​c.107C>T​(p.Pro36Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000663 in 1,206,754 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 4 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.43
• 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: Likely_benign. The variant received -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766
• BP6: Variant X-11114841-C-T is Benign according to our data. Variant chrX-11114841-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3714108.
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.107C>T	p.Pro36Leu	missense	Exon 3 of 7	NP_005324.3	P53701
	HCCS	NM_001122608.3		c.107C>T	p.Pro36Leu	missense	Exon 3 of 7	NP_001116080.1	P53701
	HCCS	NM_001171991.3		c.107C>T	p.Pro36Leu	missense	Exon 3 of 7	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.107C>T	p.Pro36Leu	missense	Exon 3 of 7	ENSP00000370139.4	P53701
	HCCS	ENST00000380763.7	TSL:1	c.107C>T	p.Pro36Leu	missense	Exon 3 of 7	ENSP00000370140.3	P53701
	HCCS	ENST00000321143.8	TSL:2	c.107C>T	p.Pro36Leu	missense	Exon 3 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111740 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183245 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000457 AC: 5 AN: 1095014 Hom.: 0 Cov.: 29 AF XY: 0.0000111 AC XY: 4 AN XY: 360466

African (AFR) AF: 0.00 AC: 0 AN: 26341

American (AMR) AF: 0.0000852 AC: 3 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839265

Other (OTH) AF: 0.0000217 AC: 1 AN: 45991

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111740 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33942

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30632

American (AMR) AF: 0.000189 AC: 2 AN: 10561

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6035

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53173

Other (OTH) AF: 0.00 AC: 0 AN: 1487

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.4
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.40		Gain of sheet (P = 0.0125)
MVP		0.93
MPC		1.2
ClinPred		0.92	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.49
gMVP		0.60
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1178817470; hg19: chrX-11132961;