rs376313818

Variant names:

• chrX-46463247-A-C
• rs376313818
• NM_001129898.2:c.192A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-46463247-A-C
• chrX-46463247-A-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001129898.2(KRABD4):​c.192A>C​(p.Glu64Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000727 in 1,210,409 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000074 (0 hom. 24 hem.)
• Consequence: KRABD4 NM_001129898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.381
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19474423).
• BS2: High Hemizygotes in GnomAd4 at 2 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.192A>C	p.Glu64Asp	missense	Exon 5 of 6	NP_001123370.1	Q5JUW0-1
	KRABD4	NM_017776.3		c.192A>C	p.Glu64Asp	missense	Exon 5 of 6	NP_060246.2	Q5JUW0-2
	KRABD4	NM_001129899.2		c.192A>C	p.Glu64Asp	missense	Exon 5 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.192A>C	p.Glu64Asp	missense	Exon 5 of 6	ENSP00000345797.4	Q5JUW0-1
	KRBOX4	ENST00000487081.1	TSL:1	c.192A>C	p.Glu64Asp	missense	Exon 4 of 6	ENSP00000418076.1	Q5JUW0-3
	KRBOX4	ENST00000942305.1		c.231A>C	p.Glu77Asp	missense	Exon 5 of 6	ENSP00000612364.1

Frequencies

GnomAD3 genomes AF: 0.0000624 AC: 7 AN: 112195 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000382 AC: 7 AN: 183407 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000855

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000738 AC: 81 AN: 1098214 Hom.: 0 Cov.: 30 AF XY: 0.0000660 AC XY: 24 AN XY: 363570

African (AFR) AF: 0.0000758 AC: 2 AN: 26401

American (AMR) AF: 0.0000568 AC: 2 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000993 AC: 3 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000855 AC: 72 AN: 842105

Other (OTH) AF: 0.0000434 AC: 2 AN: 46095

GnomAD4 genome AF: 0.0000624 AC: 7 AN: 112195 Hom.: 0 Cov.: 23 AF XY: 0.0000582 AC XY: 2 AN XY: 34363

African (AFR) AF: 0.00 AC: 0 AN: 30902

American (AMR) AF: 0.00 AC: 0 AN: 10678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6130

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

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53142

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000247 AC: 3

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	0.16
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.0041	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.38
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.069
Sift	Benign	0.034	D
Sift4G	Uncertain	0.035	D
Polyphen		0.023	B
Vest4		0.40
MutPred		0.42		Loss of loop (P = 0.0512)
MVP		0.48
MPC		0.41
ClinPred		0.40	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.082
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: rs376313818; hg19: chrX-46322682;