X-46472840-T-C

Position:

• chrX-46472840-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001129898.2(KRBOX4):​c.344T>C​(p.Leu115Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,129 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: KRBOX4 NM_001129898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.499

Genes affected

KRBOX4 (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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.171431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX4	NM_001129898.2	c.344T>C	p.Leu115Pro	missense_variant	6/6	ENST00000344302.9	NP_001123370.1
KRBOX4	NM_017776.3	c.329T>C	p.Leu110Pro	missense_variant	6/6		NP_060246.2
KRBOX4	NM_001129899.2	c.*91T>C		3_prime_UTR_variant	7/7		NP_001123371.1
KRBOX4	NM_001129900.2	c.*91T>C		3_prime_UTR_variant	7/7		NP_001123372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRBOX4	ENST00000344302.9	c.344T>C	p.Leu115Pro	missense_variant	6/6	2	NM_001129898.2	ENSP00000345797.4
KRBOX4	ENST00000487081.1	c.*88T>C		3_prime_UTR_variant	6/6	1		ENSP00000418076.1
KRBOX4	ENST00000298190.10	c.329T>C	p.Leu110Pro	missense_variant	6/6	2		ENSP00000298190.6
KRBOX4	ENST00000478600.5	c.238+9547T>C		intron_variant		2		ENSP00000418146.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098129 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363487

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.344T>C (p.L115P) alteration is located in exon 6 (coding exon 4) of the KRBOX4 gene. This alteration results from a T to C substitution at nucleotide position 344, causing the leucine (L) at amino acid position 115 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.087
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.84	P;P
Vest4		0.48
MutPred		0.53		Loss of stability (P = 0.0087);.;
MVP		0.12
MPC		0.73
ClinPred		0.86	D
GERP RS		-2.2
Varity_R		0.53
gMVP		0.18

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-46332275;