8-135457930-C-T

Position:

• chr8-135457930-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006558.3(KHDRBS3):​c.64C>T​(p.His22Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,449,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KHDRBS3 NM_006558.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

Genes affected

KHDRBS3 (HGNC:18117): (KH RNA binding domain containing, signal transduction associated 3) Enables RNA binding activity; identical protein binding activity; and protein domain specific binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome and spermatogenesis. Located in nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

LOC101927872 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDRBS3	NM_006558.3	c.64C>T	p.His22Tyr	missense_variant	1/9	ENST00000355849.10	NP_006549.1
LOC101927872	XR_002956731.2	n.46G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDRBS3	ENST00000355849.10	c.64C>T	p.His22Tyr	missense_variant	1/9	1	NM_006558.3	ENSP00000348108	P1
KHDRBS3	ENST00000704572.1	c.436C>T	p.His146Tyr	missense_variant	1/9			ENSP00000515947

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1449876 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 720604

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: 0.0000163

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jun 03, 2022

The c.64C>T (p.H22Y) alteration is located in exon 1 (coding exon 1) of the KHDRBS3 gene. This alteration results from a C to T substitution at nucleotide position 64, causing the histidine (H) at amino acid position 22 to be replaced by a tyrosine (Y). 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	Pathogenic	0.83
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.26
Sift	Benign	0.069	T
Sift4G	Benign	1.0	T
Polyphen		0.51	P
Vest4		0.41
MutPred		0.45		Gain of phosphorylation at H22 (P = 0.0458);
MVP		0.69
MPC		1.4
ClinPred		0.68	D
GERP RS		2.8
Varity_R		0.63
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr8-136470173;