rs2071134

Variant names:

• chrX-153957384-G-C
• rs2071134
• NM_005334.3:c.2283C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-153957384-G-C
• chrX-153957384-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005334.3(HCFC1):​c.2283C>G​(p.Thr761Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,205,875 control chromosomes in the GnomAD database, including 23,120 homozygotes. There are 78,932 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2181 hom., 6337 hem., cov: 23)
  • Exomes 𝑓: 0.19 (20939 hom. 72595 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.51
• Publications: 15 publications found

Genes affected

HCFC1 (HGNC:4839): (host cell factor C1) This gene is a member of the host cell factor family and encodes a protein with five Kelch repeats, a fibronectin-like motif, and six HCF repeats, each of which contains a highly specific cleavage signal. This nuclear coactivator is proteolytically cleaved at one of the six possible sites, resulting in the creation of an N-terminal chain and the corresponding C-terminal chain. The final form of this protein consists of noncovalently bound N- and C-terminal chains. The protein is involved in control of the cell cycle and transcriptional regulation during herpes simplex virus infection. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

HCFC1 Gene-Disease associations (from GenCC):

• methylmalonic acidemia with homocystinuria, type cblX

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant X-153957384-G-C is Benign according to our data. Variant chrX-153957384-G-C is described in ClinVar as Benign. ClinVar VariationId is 129218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.2283C>G	p.Thr761Thr	synonymous_variant	Exon 13 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.2283C>G	p.Thr761Thr	synonymous_variant	Exon 13 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.2283C>G	p.Thr761Thr	synonymous_variant	Exon 13 of 26	5		ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.179 AC: 19912 AN: 111036 Hom.: 2183 Cov.: 23

Gnomad AFR AF: 0.0700

Gnomad AMI AF: 0.0611

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.300 AC: 53992 AN: 179817 AF XY: 0.295

Gnomad AFR exome AF: 0.0698

Gnomad AMR exome AF: 0.579

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.752

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.188 AC: 206063 AN: 1094785 Hom.: 20939 Cov.: 32 AF XY: 0.201 AC XY: 72595 AN XY: 360753

African (AFR) AF: 0.0635 AC: 1674 AN: 26369

American (AMR) AF: 0.562 AC: 19624 AN: 34930

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 5286 AN: 19305

East Asian (EAS) AF: 0.742 AC: 22339 AN: 30088

South Asian (SAS) AF: 0.558 AC: 30122 AN: 53963

European-Finnish (FIN) AF: 0.137 AC: 5528 AN: 40426

Middle Eastern (MID) AF: 0.373 AC: 1537 AN: 4118

European-Non Finnish (NFE) AF: 0.130 AC: 109213 AN: 839662

Other (OTH) AF: 0.234 AC: 10740 AN: 45924

GnomAD4 genome AF: 0.179 AC: 19906 AN: 111090 Hom.: 2181 Cov.: 23 AF XY: 0.190 AC XY: 6337 AN XY: 33314

African (AFR) AF: 0.0699 AC: 2142 AN: 30652

American (AMR) AF: 0.403 AC: 4233 AN: 10504

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 641 AN: 2631

East Asian (EAS) AF: 0.747 AC: 2555 AN: 3420

South Asian (SAS) AF: 0.584 AC: 1514 AN: 2592

European-Finnish (FIN) AF: 0.134 AC: 805 AN: 6009

Middle Eastern (MID) AF: 0.302 AC: 65 AN: 215

European-Non Finnish (NFE) AF: 0.143 AC: 7563 AN: 52866

Other (OTH) AF: 0.229 AC: 346 AN: 1514

Alfa AF: 0.177 Hom.: 1719

Bravo AF: 0.200

EpiCase AF: 0.161

EpiControl AF: 0.157

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jun 02, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.3
DANN	Benign	0.51
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2071134; hg19: chrX-153222835; COSMIC: COSV60071861; COSMIC: COSV60071861;