NM_005334.3:c.4497+138C>T

Variant names:

• chrX-153953469-G-A
• rs762653
• NM_005334.3:c.4497+138C>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.4497+138C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 584,547 control chromosomes in the GnomAD database, including 14,707 homozygotes. There are 39,881 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., 6318 hem., cov: 24)
  • Exomes 𝑓: 0.22 (12526 hom. 33563 hem.)
• Consequence: HCFC1 NM_005334.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0880
• Publications: 4 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=-0.8).
• BP6: Variant X-153953469-G-A is Benign according to our data. Variant chrX-153953469-G-A is described in ClinVar as Benign. ClinVar VariationId is 1240591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005334.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.4497+138C>T		intron	N/A	NP_005325.2
	HCFC1	NM_001440843.1		c.4497+138C>T		intron	N/A	NP_001427772.1
	HCFC1	NM_001410705.1		c.4497+138C>T		intron	N/A	NP_001397634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4497+138C>T		intron	N/A	ENSP00000309555.7
	HCFC1	ENST00000925202.1		c.4497+138C>T		intron	N/A	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4497+138C>T		intron	N/A	ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.178 AC: 19879 AN: 111662 Hom.: 2183 Cov.: 24

Gnomad AFR AF: 0.0700

Gnomad AMI AF: 0.0600

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.218 AC: 102842 AN: 472833 Hom.: 12526 AF XY: 0.255 AC XY: 33563 AN XY: 131835

African (AFR) AF: 0.0680 AC: 880 AN: 12941

American (AMR) AF: 0.531 AC: 9864 AN: 18560

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 3004 AN: 10965

East Asian (EAS) AF: 0.740 AC: 18709 AN: 25272

South Asian (SAS) AF: 0.561 AC: 16700 AN: 29783

European-Finnish (FIN) AF: 0.134 AC: 3169 AN: 23693

Middle Eastern (MID) AF: 0.351 AC: 547 AN: 1557

European-Non Finnish (NFE) AF: 0.135 AC: 44113 AN: 325712

Other (OTH) AF: 0.240 AC: 5856 AN: 24350

GnomAD4 genome AF: 0.178 AC: 19871 AN: 111714 Hom.: 2181 Cov.: 24 AF XY: 0.186 AC XY: 6318 AN XY: 33944

African (AFR) AF: 0.0698 AC: 2160 AN: 30945

American (AMR) AF: 0.407 AC: 4334 AN: 10646

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 640 AN: 2639

East Asian (EAS) AF: 0.745 AC: 2581 AN: 3463

South Asian (SAS) AF: 0.567 AC: 1419 AN: 2502

European-Finnish (FIN) AF: 0.128 AC: 788 AN: 6141

Middle Eastern (MID) AF: 0.295 AC: 64 AN: 217

European-Non Finnish (NFE) AF: 0.142 AC: 7505 AN: 52962

Other (OTH) AF: 0.224 AC: 339 AN: 1516

Alfa AF: 0.0750 Hom.: 382

Bravo AF: 0.200

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.83
PhyloP100		-0.088
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs762653; hg19: chrX-153218920; COSMIC: COSV60072021;