rs199511876

Variant names:

• chrX-153951449-C-T
• rs199511876
• NM_005334.3:c.5418G>A

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.5418G>A​(p.Met1806Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,209,757 control chromosomes in the GnomAD database, including 2 homozygotes. There are 402 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., 23 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (2 hom. 379 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0470
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009080857).
• BP6: Variant X-153951449-C-T is Benign according to our data. Variant chrX-153951449-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 23 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.5418G>A	p.Met1806Ile	missense	Exon 22 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.5559G>A	p.Met1853Ile	missense	Exon 22 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.5553G>A	p.Met1851Ile	missense	Exon 22 of 26	NP_001397634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.5418G>A	p.Met1806Ile	missense	Exon 22 of 26	ENSP00000309555.7
	HCFC1	ENST00000369984.4	TSL:5	c.5553G>A	p.Met1851Ile	missense	Exon 22 of 26	ENSP00000359001.4
	HCFC1	ENST00000444191.5	TSL:5	c.1143G>A	p.Met381Ile	missense	Exon 6 of 10	ENSP00000399589.1

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 106 AN: 111960 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000847

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.000743 AC: 135 AN: 181717 AF XY: 0.000814

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.000936

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00105 AC: 1156 AN: 1097743 Hom.: 2 Cov.: 32 AF XY: 0.00104 AC XY: 379 AN XY: 363191

African (AFR) AF: 0.000152 AC: 4 AN: 26396

American (AMR) AF: 0.000511 AC: 18 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 32 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54145

European-Finnish (FIN) AF: 0.000347 AC: 14 AN: 40299

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4136

European-Non Finnish (NFE) AF: 0.00123 AC: 1034 AN: 841896

Other (OTH) AF: 0.000955 AC: 44 AN: 46078

GnomAD4 genome AF: 0.000946 AC: 106 AN: 112014 Hom.: 0 Cov.: 24 AF XY: 0.000672 AC XY: 23 AN XY: 34204

African (AFR) AF: 0.000130 AC: 4 AN: 30857

American (AMR) AF: 0.000846 AC: 9 AN: 10637

Ashkenazi Jewish (ASJ) AF: 0.000756 AC: 2 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.000372 AC: 1 AN: 2686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6138

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

European-Non Finnish (NFE) AF: 0.00168 AC: 89 AN: 53054

Other (OTH) AF: 0.000653 AC: 1 AN: 1532

Alfa AF: 0.000795 Hom.: 16

Bravo AF: 0.000922

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.000287 AC: 1

ESP6500EA AF: 0.00230 AC: 15

ExAC AF: 0.000976 AC: 118

EpiCase AF: 0.00213

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Methylmalonic acidemia with homocystinuria, type cblX (2)
-	-	1	HCFC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.070	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.047
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.028
Sift	Benign	0.060	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.20		Gain of methylation at K1807 (P = 0.0224)
MVP		0.24
MPC		0.60
ClinPred		0.0071	T
GERP RS		-2.5
Varity_R		0.099
gMVP		0.45
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: rs199511876; hg19: chrX-153216900;