19-6424635-C-A

Position:

• chr19-6424635-C-A

Variant summary

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

The NM_001366299.1(KHSRP):​c.67G>T​(p.Ala23Ser) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: KHSRP NM_001366299.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.164

Genes affected

KHSRP (HGNC:6316): (KH-type splicing regulatory protein) The KHSRP gene encodes a multifunctional RNA-binding protein implicated in a variety of cellular processes, including transcription, alternative pre-mRNA splicing, and mRNA localization (Min et al., 1997 [PubMed 9136930]; Gherzi et al., 2004 [PubMed 15175153]).[supplied by OMIM, Apr 2010]

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=0.0656549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHSRP	NM_001366299.1	c.67G>T	p.Ala23Ser	missense_variant	1/19	ENST00000600480.2	NP_001353228.1
KHSRP	NM_003685.3	c.67G>T	p.Ala23Ser	missense_variant	1/20		NP_003676.2
KHSRP	NM_001366300.1	c.67G>T	p.Ala23Ser	missense_variant	1/20		NP_001353229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHSRP	ENST00000600480.2	c.67G>T	p.Ala23Ser	missense_variant	1/19	2	NM_001366299.1	ENSP00000471146	A2
KHSRP	ENST00000398148.7	c.67G>T	p.Ala23Ser	missense_variant	1/20	1		ENSP00000381216	P2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 29

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

Apr 07, 2023

The c.67G>T (p.A23S) alteration is located in exon 1 (coding exon 1) of the KHSRP gene. This alteration results from a G to T substitution at nucleotide position 67, causing the alanine (A) at amino acid position 23 to be replaced by a serine (S). 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	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.030	N;.
REVEL	Benign	0.033
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.46	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.36		Gain of phosphorylation at A23 (P = 0.0011);Gain of phosphorylation at A23 (P = 0.0011);
MVP		0.35
MPC		0.99
ClinPred		0.24	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.10

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: chr19-6424646;