13-69719490-G-A

Variant names:

• chr13-69719490-G-A
• rs141275075
• NM_020866.3:c.1894C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020866.3(KLHL1):​c.1894C>T​(p.Pro632Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14
• Publications: 0 publications found

Genes affected

KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17857537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1894C>T	p.Pro632Ser	missense_variant	Exon 9 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1711C>T	p.Pro571Ser	missense_variant	Exon 8 of 10		NP_001273654.1
KLHL1	XM_017020678.3	c.1375C>T	p.Pro459Ser	missense_variant	Exon 9 of 11		XP_016876167.1
KLHL1	XM_017020679.2	c.1225C>T	p.Pro409Ser	missense_variant	Exon 9 of 11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.1894C>T	p.Pro632Ser	missense_variant	Exon 9 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1711C>T	p.Pro571Ser	missense_variant	Exon 8 of 10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151888 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250992 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461406 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.000649 AC: 29 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111700

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151888 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74140

African (AFR) AF: 0.00 AC: 0 AN: 41364

American (AMR) AF: 0.000263 AC: 4 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1894C>T (p.P632S) alteration is located in exon 9 (coding exon 9) of the KLHL1 gene. This alteration results from a C to T substitution at nucleotide position 1894, causing the proline (P) at amino acid position 632 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	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.12	N;.
PhyloP100		8.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.5	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.12	T;.
Sift4G	Benign	0.29	T;T
Polyphen		0.51	P;.
Vest4		0.48
MutPred		0.51		Gain of catalytic residue at P632 (P = 0);.;
MVP		0.87
MPC		0.23
ClinPred		0.30	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.45
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs141275075; hg19: chr13-70293622;