3-42942630-G-C

Position:

• chr3-42942630-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001205272.2(KRBOX1):​c.370G>C​(p.Asp124His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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: 32)
• Consequence: KRBOX1 NM_001205272.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

Genes affected

KRBOX1 (HGNC:38708): (KRAB box domain containing 1) Predicted to be involved in regulation of transcription, DNA-templated. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000290317 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05411774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX1	NM_001205272.2	c.370G>C	p.Asp124His	missense_variant	5/5	ENST00000383748.9	NP_001192201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRBOX1	ENST00000383748.9	c.370G>C	p.Asp124His	missense_variant	5/5	1	NM_001205272.2	ENSP00000373254.5
ENSG00000290317	ENST00000426937.5	c.370G>C	p.Asp124His	missense_variant	7/7	3		ENSP00000413859.1
ENSG00000273291	ENST00000446977.2	c.277+559G>C		intron_variant		4		ENSP00000477043.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 32

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

Oct 24, 2024

The c.370G>C (p.D124H) alteration is located in exon 5 (coding exon 4) of the KRBOX1 gene. This alteration results from a G to C substitution at nucleotide position 370, causing the aspartic acid (D) at amino acid position 124 to be replaced by a histidine (H). 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	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.48	.;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.073
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.033	B;B;B
Vest4		0.35
MutPred		0.26		Gain of methylation at K127 (P = 0.0495);Gain of methylation at K127 (P = 0.0495);Gain of methylation at K127 (P = 0.0495);
MVP		0.014
MPC		0.45
ClinPred		0.16	T
GERP RS		0.22
Varity_R		0.071
gMVP		0.060

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: chr3-42984122;