rs782138046

Variant names:

• chrX-153954084-T-G
• rs782138046
• NM_005334.3:c.4315A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001440843.1(HCFC1):​c.4315A>C​(p.Asn1439His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,088,600 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000033 (0 hom. 12 hem.)
• Consequence: HCFC1 NM_001440843.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.43
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25108328).
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440843.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.4315A>C	p.Asn1439His	missense	Exon 17 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.4315A>C	p.Asn1439His	missense	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.4315A>C	p.Asn1439His	missense	Exon 17 of 26	NP_001397634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4315A>C	p.Asn1439His	missense	Exon 17 of 26	ENSP00000309555.7
	HCFC1	ENST00000925202.1		c.4315A>C	p.Asn1439His	missense	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4315A>C	p.Asn1439His	missense	Exon 17 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000173 AC: 3 AN: 173189 AF XY: 0.0000165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000331 AC: 36 AN: 1088600 Hom.: 0 Cov.: 31 AF XY: 0.0000337 AC XY: 12 AN XY: 356108

African (AFR) AF: 0.00 AC: 0 AN: 26224

American (AMR) AF: 0.00 AC: 0 AN: 34611

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19031

East Asian (EAS) AF: 0.00 AC: 0 AN: 29983

South Asian (SAS) AF: 0.00 AC: 0 AN: 53419

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4025

European-Non Finnish (NFE) AF: 0.0000431 AC: 36 AN: 835711

Other (OTH) AF: 0.00 AC: 0 AN: 45658

GnomAD4 genome Cov.: 25

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Methylmalonic acidemia with homocystinuria, type cblX (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.79
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.028	D
Polyphen		0.98	D
Vest4		0.26
MutPred		0.18		Gain of catalytic residue at N1439 (P = 0.0715)
MVP		0.76
MPC		1.5
ClinPred		0.52	D
GERP RS		5.9
PromoterAI		-0.079	Neutral
Varity_R		0.45
gMVP		0.44
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782138046; hg19: chrX-153219535;