rs17422

Variant names:

• chrX-153961975-A-G
• rs17422
• NM_005334.3:c.797+247T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-153961975-A-G
• chrX-153961975-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005334.3(HCFC1):​c.797+247T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 111,255 control chromosomes in the GnomAD database, including 8,004 homozygotes. There are 12,775 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 (8004 hom., 12775 hem., cov: 23)
• Consequence: HCFC1 NM_005334.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.933
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-153961975-A-G is Benign according to our data. Variant chrX-153961975-A-G is described in ClinVar as Benign. ClinVar VariationId is 671518.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.797+247T>C		intron_variant	Intron 5 of 25	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.797+247T>C		intron_variant	Intron 5 of 25	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.797+247T>C		intron_variant	Intron 5 of 25	5		ENSP00000359001.4
HCFC1	ENST00000461098.1	n.46+247T>C		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.382 AC: 42447 AN: 111198 Hom.: 7994 Cov.: 23

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.403

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.382 AC: 42508 AN: 111255 Hom.: 8004 Cov.: 23 AF XY: 0.382 AC XY: 12775 AN XY: 33485

African (AFR) AF: 0.687 AC: 20936 AN: 30456

American (AMR) AF: 0.498 AC: 5264 AN: 10573

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 680 AN: 2634

East Asian (EAS) AF: 0.759 AC: 2651 AN: 3493

South Asian (SAS) AF: 0.598 AC: 1587 AN: 2655

European-Finnish (FIN) AF: 0.178 AC: 1083 AN: 6075

Middle Eastern (MID) AF: 0.361 AC: 78 AN: 216

European-Non Finnish (NFE) AF: 0.180 AC: 9552 AN: 52943

Other (OTH) AF: 0.412 AC: 628 AN: 1524

Alfa AF: 0.260 Hom.: 6767

Bravo AF: 0.424

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.72
DANN	Benign	0.61
PhyloP100		-0.93
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: rs17422; hg19: chrX-153227426;