19-6424542-A-G

Position:

• chr19-6424542-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001366299.1(KHSRP):​c.160T>C​(p.Ser54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 830,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 29)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: KHSRP NM_001366299.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0960

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07739183).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHSRP	NM_001366299.1	c.160T>C	p.Ser54Pro	missense_variant	1/19	ENST00000600480.2	NP_001353228.1
KHSRP	NM_003685.3	c.160T>C	p.Ser54Pro	missense_variant	1/20		NP_003676.2
KHSRP	NM_001366300.1	c.160T>C	p.Ser54Pro	missense_variant	1/20		NP_001353229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHSRP	ENST00000600480.2	c.160T>C	p.Ser54Pro	missense_variant	1/19	2	NM_001366299.1	ENSP00000471146.2
KHSRP	ENST00000398148.7	c.160T>C	p.Ser54Pro	missense_variant	1/20	1		ENSP00000381216.2
KHSRP	ENST00000599395.5	c.-15T>C		upstream_gene_variant		5		ENSP00000471262.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000301 AC: 25 AN: 830806 Hom.: 0 Cov.: 19 AF XY: 0.0000286 AC XY: 11 AN XY: 384178

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: 0.0000330

Gnomad4 OTH exome AF: 0.00

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

Dec 03, 2024

The c.160T>C (p.S54P) alteration is located in exon 1 (coding exon 1) of the KHSRP gene. This alteration results from a T to C substitution at nucleotide position 160, causing the serine (S) at amino acid position 54 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	0.071
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.41
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.40	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.029
Sift	Benign	0.11	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.056	B;.
Vest4		0.13
MutPred		0.24		Loss of phosphorylation at S54 (P = 0.0017);Loss of phosphorylation at S54 (P = 0.0017);
MVP		0.30
MPC		1.3
ClinPred		0.071	T
GERP RS		0.53
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Varity_R		0.16
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs1003898749; hg19: chr19-6424553;