chrX-153949406-A-G

Variant names:

• chrX-153949406-A-G
• rs377160085
• NM_005334.3:c.6069-20T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005334.3(HCFC1):​c.6069-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000325 in 1,198,834 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000035 (0 hom. 13 hem.)
• Consequence: HCFC1 NM_005334.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.146
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-153949406-A-G is Benign according to our data. Variant chrX-153949406-A-G is described in ClinVar as Benign. ClinVar VariationId is 2716475.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 13 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.6069-20T>C		intron	N/A	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.6210-20T>C		intron	N/A	NP_001427772.1
	HCFC1	NM_001410705.1		c.6204-20T>C		intron	N/A	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.6069-20T>C		intron	N/A	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.6210-20T>C		intron	N/A	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.6204-20T>C		intron	N/A	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110908 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000614 AC: 11 AN: 179138 AF XY: 0.0000458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000673

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.0000349 AC: 38 AN: 1087926 Hom.: 0 Cov.: 29 AF XY: 0.0000367 AC XY: 13 AN XY: 353920

African (AFR) AF: 0.00 AC: 0 AN: 26205

American (AMR) AF: 0.00 AC: 0 AN: 35000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19267

East Asian (EAS) AF: 0.000862 AC: 26 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 53825

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39977

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833640

Other (OTH) AF: 0.000240 AC: 11 AN: 45740

GnomAD4 genome AF: 0.00000902 AC: 1 AN: 110908 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33116

African (AFR) AF: 0.00 AC: 0 AN: 30395

American (AMR) AF: 0.00 AC: 0 AN: 10599

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3518

South Asian (SAS) AF: 0.00 AC: 0 AN: 2602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5963

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52786

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000718

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	-0.85
CADD	Benign	1.4
DANN	Benign	0.32
PhyloP100		-0.15
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: rs377160085; hg19: chrX-153214857;