chrX-153949359-G-A

Variant names:

• chrX-153949359-G-A
• rs782174121
• NM_005334.3:c.6096C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_005334.3(HCFC1):​c.6096C>T​(p.Ala2032Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,204,963 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000028 (0 hom. 19 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.109
• Publications: 1 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: Ambry Genetics, Orphanet, G2P, 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-153949359-G-A is Benign according to our data. Variant chrX-153949359-G-A is described in ClinVar as Benign. ClinVar VariationId is 2997301.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.109 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.6096C>T	p.Ala2032Ala	synonymous	Exon 26 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.6237C>T	p.Ala2079Ala	synonymous	Exon 26 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.6231C>T	p.Ala2077Ala	synonymous	Exon 26 of 26	NP_001397634.1	A6NEM2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.6096C>T	p.Ala2032Ala	synonymous	Exon 26 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.6237C>T	p.Ala2079Ala	synonymous	Exon 26 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.6231C>T	p.Ala2077Ala	synonymous	Exon 26 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110460 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000390

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000222 AC: 4 AN: 180276 AF XY: 0.0000301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000746

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000283 AC: 31 AN: 1094503 Hom.: 0 Cov.: 29 AF XY: 0.0000527 AC XY: 19 AN XY: 360341

African (AFR) AF: 0.00 AC: 0 AN: 26307

American (AMR) AF: 0.00 AC: 0 AN: 35073

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19351

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30192

South Asian (SAS) AF: 0.000278 AC: 15 AN: 54026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 839468

Other (OTH) AF: 0.0000435 AC: 2 AN: 45964

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110460 Hom.: 0 Cov.: 22 AF XY: 0.0000612 AC XY: 2 AN XY: 32686

African (AFR) AF: 0.00 AC: 0 AN: 30274

American (AMR) AF: 0.00 AC: 0 AN: 10501

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.000390 AC: 1 AN: 2561

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5873

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52704

Other (OTH) AF: 0.00 AC: 0 AN: 1493

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.2
DANN	Benign	0.85
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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: rs782174121; hg19: chrX-153214810;