chrX-46472758-C-G

Variant names:

• chrX-46472758-C-G
• rs751467099
• NM_001129898.2:c.262C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001129898.2(KRABD4):​c.262C>G​(p.Gln88Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000755 in 1,205,698 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000081 (0 hom. 31 hem.)
• Consequence: KRABD4 NM_001129898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.66
• Publications: 1 publications found

Genes affected

KRABD4 (HGNC:26007): (KRAB box domain containing 4) This encodes a zinc finger protein with an N-terminal KRAB (Kruppel-associated) domain found in transcriptional repressors. This gene is located in a region of the X chromosome thought to be involved in nonsyndromic X-linked cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039812654).
• BS2: High Hemizygotes in GnomAdExome4 at 31 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129898.2. 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
	KRABD4	NM_001129898.2	MANE Select	c.262C>G	p.Gln88Glu	missense	Exon 6 of 6	NP_001123370.1	Q5JUW0-1
	KRABD4	NM_017776.3		c.247C>G	p.Gln83Glu	missense	Exon 6 of 6	NP_060246.2	Q5JUW0-2
	KRABD4	NM_001129899.2		c.*9C>G		3_prime_UTR	Exon 7 of 7	NP_001123371.1	Q5JUW0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRBOX4	ENST00000344302.9	TSL:2 MANE Select	c.262C>G	p.Gln88Glu	missense	Exon 6 of 6	ENSP00000345797.4	Q5JUW0-1
	KRBOX4	ENST00000487081.1	TSL:1	c.*6C>G		3_prime_UTR	Exon 6 of 6	ENSP00000418076.1	Q5JUW0-3
	KRBOX4	ENST00000942305.1		c.286C>G	p.Gln96Glu	missense	Exon 6 of 6	ENSP00000612364.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111301 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: 0.000566

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: 0.0000393 AC: 7 AN: 178251 AF XY: 0.0000631

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000511

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000813 AC: 89 AN: 1094397 Hom.: 0 Cov.: 30 AF XY: 0.0000860 AC XY: 31 AN XY: 360313

African (AFR) AF: 0.00 AC: 0 AN: 26245

American (AMR) AF: 0.00 AC: 0 AN: 34554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19181

East Asian (EAS) AF: 0.00292 AC: 88 AN: 30184

South Asian (SAS) AF: 0.00 AC: 0 AN: 53131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40498

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

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840541

Other (OTH) AF: 0.00 AC: 0 AN: 45953

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111301 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33509

African (AFR) AF: 0.00 AC: 0 AN: 30612

American (AMR) AF: 0.00 AC: 0 AN: 10377

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.000566 AC: 2 AN: 3533

South Asian (SAS) AF: 0.00 AC: 0 AN: 2656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5943

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53110

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.7
DANN	Benign	0.97
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.012	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.47	N
PhyloP100		-2.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.037
Sift	Benign	0.22	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.34		Gain of loop (P = 0.0166)
MVP		0.58
MPC		0.48
ClinPred		0.048	T
GERP RS		1.5
Varity_R		0.24
gMVP		0.035
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs751467099; hg19: chrX-46332193; COSMIC: COSV53344075; COSMIC: COSV53344075;