13-69707762-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020866.3(KLHL1):c.2050G>T(p.Ala684Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,568 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2998196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL1	NM_020866.3	c.2050G>T	p.Ala684Ser	missense_variant	10/11	ENST00000377844.9
KLHL1	NM_001286725.2	c.1867G>T	p.Ala623Ser	missense_variant	9/10
KLHL1	XM_017020678.3	c.1531G>T	p.Ala511Ser	missense_variant	10/11
KLHL1	XM_017020679.2	c.1381G>T	p.Ala461Ser	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL1	ENST00000377844.9	c.2050G>T	p.Ala684Ser	missense_variant	10/11	1	NM_020866.3	P1
KLHL1	ENST00000545028.2	c.1867G>T	p.Ala623Ser	missense_variant	9/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460568 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726594

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 17, 2023

The c.2050G>T (p.A684S) alteration is located in exon 10 (coding exon 10) of the KLHL1 gene. This alteration results from a G to T substitution at nucleotide position 2050, causing the alanine (A) at amino acid position 684 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	0.098
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	0.030
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.23
Sift	Benign	0.099	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.010	B;.
Vest4		0.21
MutPred		0.48		Gain of catalytic residue at L686 (P = 0.0836);.;
MVP		0.73
MPC		0.33
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.19
gMVP		0.26

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: chr13-70281894; COSMIC: COSV64770404;