X-153954214-C-T

Variant names:

• chrX-153954214-C-T
• rs2071133
• NM_005334.3:c.4185G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005334.3(HCFC1):​c.4185G>A​(p.Ala1395Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,205,918 control chromosomes in the GnomAD database, including 27,269 homozygotes. There are 91,326 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (2573 hom., 7135 hem., cov: 24)
  • Exomes 𝑓: 0.22 (24696 hom. 84191 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.78
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-153954214-C-T is Benign according to our data. Variant chrX-153954214-C-T is described in ClinVar as Benign. ClinVar VariationId is 95280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.736 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.4185G>A	p.Ala1395Ala	synonymous	Exon 17 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.4185G>A	p.Ala1395Ala	synonymous	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.4185G>A	p.Ala1395Ala	synonymous	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.4185G>A	p.Ala1395Ala	synonymous	Exon 17 of 26	ENSP00000309555.7
	HCFC1	ENST00000925202.1		c.4185G>A	p.Ala1395Ala	synonymous	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4185G>A	p.Ala1395Ala	synonymous	Exon 17 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.211 AC: 23129 AN: 109666 Hom.: 2567 Cov.: 24

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0666

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.328 AC: 58117 AN: 177373 AF XY: 0.325

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.592

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.762

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.220 AC: 241644 AN: 1096205 Hom.: 24696 Cov.: 34 AF XY: 0.232 AC XY: 84191 AN XY: 362177

African (AFR) AF: 0.108 AC: 2836 AN: 26380

American (AMR) AF: 0.572 AC: 20016 AN: 34976

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 5501 AN: 19346

East Asian (EAS) AF: 0.748 AC: 22582 AN: 30179

South Asian (SAS) AF: 0.568 AC: 30734 AN: 54084

European-Finnish (FIN) AF: 0.176 AC: 7004 AN: 39787

Middle Eastern (MID) AF: 0.381 AC: 1544 AN: 4048

European-Non Finnish (NFE) AF: 0.166 AC: 139299 AN: 841382

Other (OTH) AF: 0.264 AC: 12128 AN: 46023

GnomAD4 genome AF: 0.211 AC: 23136 AN: 109713 Hom.: 2573 Cov.: 24 AF XY: 0.221 AC XY: 7135 AN XY: 32267

African (AFR) AF: 0.111 AC: 3338 AN: 30099

American (AMR) AF: 0.424 AC: 4434 AN: 10460

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 666 AN: 2612

East Asian (EAS) AF: 0.760 AC: 2591 AN: 3409

South Asian (SAS) AF: 0.590 AC: 1506 AN: 2553

European-Finnish (FIN) AF: 0.172 AC: 993 AN: 5772

Middle Eastern (MID) AF: 0.321 AC: 67 AN: 209

European-Non Finnish (NFE) AF: 0.174 AC: 9097 AN: 52422

Other (OTH) AF: 0.266 AC: 399 AN: 1501

Alfa AF: 0.203 Hom.: 2672

Bravo AF: 0.230

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Methylmalonic acidemia with homocystinuria, type cblX (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.092
DANN	Benign	0.45
PhyloP100		-2.8
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs2071133; hg19: chrX-153219665; COSMIC: COSV60069027; COSMIC: COSV60069027;