11-75425493-G-A

Position:

• chr11-75425493-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039548.3(KLHL35):​c.1274C>T​(p.Ala425Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000354 in 1,410,504 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KLHL35 NM_001039548.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81

Genes affected

KLHL35 (HGNC:26597): (kelch like family member 35)

KLHL35 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL35	NM_001039548.3	c.1274C>T	p.Ala425Val	missense_variant	5/7	ENST00000539798.3	NP_001034637.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL35	ENST00000539798.3	c.1274C>T	p.Ala425Val	missense_variant	5/7	1	NM_001039548.3	ENSP00000438526.1
KLHL35	ENST00000376292.8	c.614C>T	p.Ala205Val	missense_variant	4/6	1		ENSP00000365469.4
KLHL35	ENST00000460787.1	n.1669C>T		non_coding_transcript_exon_variant	3/5	2
KLHL35	ENST00000527491.1	n.*13C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1410504 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 699756

Gnomad4 AFR exome AF: 0.0000974

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: 0.00

Gnomad4 OTH exome AF: 0.0000342

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Nov 12, 2024

The c.1274C>T (p.A425V) alteration is located in exon 4 (coding exon 4) of the KLHL35 gene. This alteration results from a C to T substitution at nucleotide position 1274, causing the alanine (A) at amino acid position 425 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.052	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.4	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D;T
Sift4G	Uncertain	0.010	D;D
Vest4		0.32
MVP		0.65
MPC		0.072
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.060
gMVP		0.45

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: rs1431920189; hg19: chr11-75136538;