rs2071132

Variant names:

• chrX-153950585-G-A
• rs2071132
• NM_005334.3:c.5704-42C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153950585-G-A
• chrX-153950585-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005334.3(HCFC1):​c.5704-42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,098,077 control chromosomes in the GnomAD database, including 35,729 homozygotes. There are 90,561 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (7973 hom., 12973 hem., cov: 24)
  • Exomes 𝑓: 0.24 (27756 hom. 77588 hem.)
• Consequence: HCFC1 NM_005334.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.194
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-153950585-G-A is Benign according to our data. Variant chrX-153950585-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.5704-42C>T		intron_variant	Intron 23 of 25	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.5704-42C>T		intron_variant	Intron 23 of 25	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.5839-42C>T		intron_variant	Intron 23 of 25	5		ENSP00000359001.4
HCFC1	ENST00000444191.5	c.1429-42C>T		intron_variant	Intron 7 of 9	5		ENSP00000399589.1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 42596 AN: 111543 Hom.: 7963 Cov.: 24

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.0689

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.349

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.401

GnomAD2 exomes AF: 0.377 AC: 47413 AN: 125673 AF XY: 0.348

Gnomad AFR exome AF: 0.701

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.761

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.242 AC: 238746 AN: 986480 Hom.: 27756 Cov.: 22 AF XY: 0.266 AC XY: 77588 AN XY: 292138

African (AFR) AF: 0.701 AC: 16409 AN: 23404

American (AMR) AF: 0.604 AC: 14523 AN: 24036

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 4316 AN: 14769

East Asian (EAS) AF: 0.750 AC: 22157 AN: 29530

South Asian (SAS) AF: 0.577 AC: 25477 AN: 44181

European-Finnish (FIN) AF: 0.179 AC: 6617 AN: 36925

Middle Eastern (MID) AF: 0.423 AC: 1530 AN: 3614

European-Non Finnish (NFE) AF: 0.175 AC: 134808 AN: 768258

Other (OTH) AF: 0.309 AC: 12909 AN: 41763

GnomAD4 genome AF: 0.382 AC: 42656 AN: 111597 Hom.: 7973 Cov.: 24 AF XY: 0.383 AC XY: 12973 AN XY: 33831

African (AFR) AF: 0.687 AC: 21051 AN: 30632

American (AMR) AF: 0.498 AC: 5293 AN: 10624

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 675 AN: 2644

East Asian (EAS) AF: 0.760 AC: 2663 AN: 3505

South Asian (SAS) AF: 0.594 AC: 1606 AN: 2704

European-Finnish (FIN) AF: 0.175 AC: 1067 AN: 6086

Middle Eastern (MID) AF: 0.355 AC: 75 AN: 211

European-Non Finnish (NFE) AF: 0.180 AC: 9554 AN: 52987

Other (OTH) AF: 0.411 AC: 625 AN: 1522

Alfa AF: 0.261 Hom.: 3844

Bravo AF: 0.423

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.28
DANN	Benign	0.20
PhyloP100		-0.19
Mutation Taster		=100/0	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: rs2071132; hg19: chrX-153216036; COSMIC: COSV60069272;