13-69940045-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020866.3(KLHL1):c.1009A>G(p.Thr337Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,451,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL1	NM_020866.3	c.1009A>G	p.Thr337Ala	missense_variant	4/11	ENST00000377844.9
KLHL1	NM_001286725.2	c.826A>G	p.Thr276Ala	missense_variant	3/10
KLHL1	XM_017020678.3	c.490A>G	p.Thr164Ala	missense_variant	4/11
KLHL1	XM_017020679.2	c.340A>G	p.Thr114Ala	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL1	ENST00000377844.9	c.1009A>G	p.Thr337Ala	missense_variant	4/11	1	NM_020866.3	P1
KLHL1	ENST00000545028.2	c.826A>G	p.Thr276Ala	missense_variant	3/10	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242050 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000342

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451784 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 722166

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.0000167

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

Aug 10, 2021

The c.1009A>G (p.T337A) alteration is located in exon 4 (coding exon 4) of the KLHL1 gene. This alteration results from a A to G substitution at nucleotide position 1009, causing the threonine (T) at amino acid position 337 to be replaced by an alanine (A). 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	0.26
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.84	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.60
Sift	Benign	0.047	D;.
Sift4G	Benign	0.16	T;T
Polyphen		0.87	P;.
Vest4		0.82
MutPred		0.59		Gain of catalytic residue at A333 (P = 0.0266);.;
MVP		0.84
MPC		0.14
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.44

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: rs1414295255; hg19: chr13-70514177;