X-46472847-T-A

Variant names:

• chrX-46472847-T-A
• rs373750614
• NM_001129898.2:c.351T>A

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.351T>A​(p.Asp117Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000826 in 1,210,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: KRABD4 NM_001129898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.822
• 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=0.07964036).
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.351T>A	p.Asp117Glu	missense	Exon 6 of 6	NP_001123370.1	Q5JUW0-1
	KRABD4	NM_017776.3		c.336T>A	p.Asp112Glu	missense	Exon 6 of 6	NP_060246.2	Q5JUW0-2
	KRABD4	NM_001129899.2		c.*98T>A		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.351T>A	p.Asp117Glu	missense	Exon 6 of 6	ENSP00000345797.4	Q5JUW0-1
	KRBOX4	ENST00000487081.1	TSL:1	c.*95T>A		3_prime_UTR	Exon 6 of 6	ENSP00000418076.1	Q5JUW0-3
	KRBOX4	ENST00000942305.1		c.375T>A	p.Asp125Glu	missense	Exon 6 of 6	ENSP00000612364.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111999 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000974

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183290 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000152

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000637 AC: 7 AN: 1098186 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 3 AN XY: 363546

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000265 AC: 7 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842086

Other (OTH) AF: 0.00 AC: 0 AN: 46093

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000768718), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111999 Hom.: 0 Cov.: 22 AF XY: 0.0000293 AC XY: 1 AN XY: 34157

African (AFR) AF: 0.0000974 AC: 3 AN: 30808

American (AMR) AF: 0.00 AC: 0 AN: 10507

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6073

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53237

Other (OTH) AF: 0.00 AC: 0 AN: 1522

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

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	-0.52	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.0037	T
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.085	N
PhyloP100		0.82
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.046
Sift	Benign	0.82	T
Sift4G	Benign	1.0	T
Polyphen		0.98	D
Vest4		0.17
MutPred		0.30		Gain of disorder (P = 0.129)
MVP		0.48
MPC		1.3
ClinPred		0.11	T
GERP RS		-0.21
Varity_R		0.081
gMVP		0.011
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: rs373750614; hg19: chrX-46332282;