X-153954909-A-G

Variant names:

• chrX-153954909-A-G
• rs1051152
• NM_005334.3:c.3490T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005334.3(HCFC1):​c.3490T>C​(p.Ser1164Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,169,617 control chromosomes in the GnomAD database, including 37,426 homozygotes. There are 97,476 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1164T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.38 (7971 hom., 12912 hem., cov: 24)
  • Exomes 𝑓: 0.24 (29455 hom. 84564 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.650
• Publications: 30 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4520427E-6).
• BP6: Variant X-153954909-A-G is Benign according to our data. Variant chrX-153954909-A-G is described in ClinVar as Benign. ClinVar VariationId is 95278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 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.3490T>C	p.Ser1164Pro	missense	Exon 17 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.3490T>C	p.Ser1164Pro	missense	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.3490T>C	p.Ser1164Pro	missense	Exon 17 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.3490T>C	p.Ser1164Pro	missense	Exon 17 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.3490T>C	p.Ser1164Pro	missense	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.3490T>C	p.Ser1164Pro	missense	Exon 17 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.383 AC: 42496 AN: 111025 Hom.: 7962 Cov.: 24

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.0682

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.353

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.407

GnomAD2 exomes AF: 0.387 AC: 46926 AN: 121239 AF XY: 0.379

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.239 AC: 252780 AN: 1058535 Hom.: 29455 Cov.: 34 AF XY: 0.247 AC XY: 84564 AN XY: 341803

African (AFR) AF: 0.694 AC: 17841 AN: 25695

American (AMR) AF: 0.598 AC: 18126 AN: 30294

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 5320 AN: 18621

East Asian (EAS) AF: 0.750 AC: 21522 AN: 28704

South Asian (SAS) AF: 0.572 AC: 29172 AN: 50959

European-Finnish (FIN) AF: 0.176 AC: 5451 AN: 31026

Middle Eastern (MID) AF: 0.402 AC: 1341 AN: 3337

European-Non Finnish (NFE) AF: 0.170 AC: 140243 AN: 825211

Other (OTH) AF: 0.308 AC: 13764 AN: 44688

GnomAD4 genome AF: 0.383 AC: 42556 AN: 111082 Hom.: 7971 Cov.: 24 AF XY: 0.387 AC XY: 12912 AN XY: 33384

African (AFR) AF: 0.687 AC: 21007 AN: 30590

American (AMR) AF: 0.500 AC: 5362 AN: 10732

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 677 AN: 2632

East Asian (EAS) AF: 0.762 AC: 2593 AN: 3402

South Asian (SAS) AF: 0.607 AC: 1620 AN: 2670

European-Finnish (FIN) AF: 0.179 AC: 1077 AN: 6007

Middle Eastern (MID) AF: 0.359 AC: 78 AN: 217

European-Non Finnish (NFE) AF: 0.180 AC: 9464 AN: 52637

Other (OTH) AF: 0.416 AC: 632 AN: 1521

Alfa AF: 0.253 Hom.: 12897

Bravo AF: 0.423

TwinsUK AF: 0.175 AC: 650

ALSPAC AF: 0.174 AC: 503

ESP6500AA AF: 0.638 AC: 2283

ESP6500EA AF: 0.180 AC: 1169

ExAC AF: 0.332 AC: 37527

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Methylmalonic acidemia with homocystinuria, type cblX (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	9.5
DANN	Benign	0.13
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	N
PhyloP100		0.65
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.69
ClinPred		0.00095	T
GERP RS		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.11
gMVP		0.26
Mutation Taster		=97/3	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: rs1051152; hg19: chrX-153220360; COSMIC: COSV60071925; COSMIC: COSV60071925;