X-46472872-T-G

Variant names:

• chrX-46472872-T-G
• rs996998674
• NM_001129898.2:c.376T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001129898.2(KRABD4):​c.376T>G​(p.Cys126Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,784 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: KRABD4 NM_001129898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.951
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28674203).

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.376T>G	p.Cys126Gly	missense	Exon 6 of 6	NP_001123370.1	Q5JUW0-1
	KRABD4	NM_017776.3		c.361T>G	p.Cys121Gly	missense	Exon 6 of 6	NP_060246.2	Q5JUW0-2
	KRABD4	NM_001129899.2		c.*123T>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.376T>G	p.Cys126Gly	missense	Exon 6 of 6	ENSP00000345797.4	Q5JUW0-1
	KRBOX4	ENST00000487081.1	TSL:1	c.*120T>G		3_prime_UTR	Exon 6 of 6	ENSP00000418076.1	Q5JUW0-3
	KRBOX4	ENST00000942305.1		c.400T>G	p.Cys134Gly	missense	Exon 6 of 6	ENSP00000612364.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111784 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

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: 0.00000546 AC: 1 AN: 183263 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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 Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1098188 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363546

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.0000284 AC: 1 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

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

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: 842087

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111784 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33962

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

African (AFR) AF: 0.0000326 AC: 1 AN: 30720

American (AMR) AF: 0.00 AC: 0 AN: 10529

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6011

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53177

Other (OTH) AF: 0.00 AC: 0 AN: 1513

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.3
DANN	Benign	0.77
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.95
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.66	P
Vest4		0.25
MutPred		0.74		Loss of stability (P = 0.0021)
MVP		0.092
MPC		0.58
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.039
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs996998674; hg19: chrX-46332307;