rs189548179

Variant names:

• chrX-153954605-G-A
• rs189548179
• NM_005334.3:c.3794C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005334.3(HCFC1):​c.3794C>T​(p.Ser1265Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,208,001 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 332 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1265S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 45 hem., cov: 25)
  • Exomes 𝑓: 0.00090 (0 hom. 287 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.67
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054138303).
• BP6: Variant X-153954605-G-A is Benign according to our data. Variant chrX-153954605-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 45 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.3794C>T	p.Ser1265Leu	missense	Exon 17 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.3794C>T	p.Ser1265Leu	missense	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.3794C>T	p.Ser1265Leu	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.3794C>T	p.Ser1265Leu	missense	Exon 17 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.3794C>T	p.Ser1265Leu	missense	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.3794C>T	p.Ser1265Leu	missense	Exon 17 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 176 AN: 112645 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000645

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000659

Gnomad OTH AF: 0.00196

GnomAD2 exomes AF: 0.000736 AC: 130 AN: 176610 AF XY: 0.000734

Gnomad AFR exome AF: 0.00409

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000615

Gnomad OTH exome AF: 0.000923

GnomAD4 exome AF: 0.000904 AC: 990 AN: 1095305 Hom.: 0 Cov.: 34 AF XY: 0.000795 AC XY: 287 AN XY: 361129

African (AFR) AF: 0.00303 AC: 80 AN: 26362

American (AMR) AF: 0.000371 AC: 13 AN: 35079

Ashkenazi Jewish (ASJ) AF: 0.00224 AC: 43 AN: 19235

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 54000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39803

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.000946 AC: 795 AN: 840557

Other (OTH) AF: 0.00128 AC: 59 AN: 45973

GnomAD4 genome AF: 0.00155 AC: 175 AN: 112696 Hom.: 0 Cov.: 25 AF XY: 0.00129 AC XY: 45 AN XY: 34886

African (AFR) AF: 0.00402 AC: 125 AN: 31095

American (AMR) AF: 0.000645 AC: 7 AN: 10860

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6287

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000659 AC: 35 AN: 53077

Other (OTH) AF: 0.00194 AC: 3 AN: 1548

Alfa AF: 0.00338 Hom.: 13

Bravo AF: 0.00157

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00138 AC: 5

ESP6500EA AF: 0.00122 AC: 8

ExAC AF: 0.000695 AC: 84

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Genetic developmental and epileptic encephalopathy (1)
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.079
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.048
MVP		0.14
MPC		0.48
ClinPred		0.0045	T
GERP RS		4.2
PromoterAI		0.015	Neutral
Varity_R		0.037
gMVP		0.46
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: rs189548179; hg19: chrX-153220056; COSMIC: COSV99080104; COSMIC: COSV99080104;