NM_005334.3:c.4086C>T

Variant names:

• chrX-153954313-G-A
• rs1388599232
• NM_005334.3:c.4086C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_005334.3(HCFC1):​c.4086C>T​(p.Thr1362Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,066 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 25)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.220
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=0.22 with no splicing effect.

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.4086C>T	p.Thr1362Thr	synonymous	Exon 17 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.4086C>T	p.Thr1362Thr	synonymous	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.4086C>T	p.Thr1362Thr	synonymous	Exon 17 of 26	NP_001397634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4086C>T	p.Thr1362Thr	synonymous	Exon 17 of 26	ENSP00000309555.7
	HCFC1	ENST00000369984.4	TSL:5	c.4086C>T	p.Thr1362Thr	synonymous	Exon 17 of 26	ENSP00000359001.4
	HCFC1	ENST00000444191.5	TSL:5	c.-193C>T		upstream_gene	N/A	ENSP00000399589.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112066 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000931

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

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112066 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34354

African (AFR) AF: 0.00 AC: 0 AN: 30789

American (AMR) AF: 0.0000931 AC: 1 AN: 10746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.00 AC: 0 AN: 2704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53085

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Kabuki syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.9
DANN	Benign	0.67
PhyloP100		0.22
PromoterAI		-0.0068	Neutral

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: rs1388599232; hg19: chrX-153219764;