chr13-69707771-T-C

Position:

• chr13-69707771-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.2041A>G​(p.Thr681Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

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, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.2041A>G	p.Thr681Ala	missense_variant	10/11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1858A>G	p.Thr620Ala	missense_variant	9/10		NP_001273654.1
KLHL1	XM_017020678.3	c.1522A>G	p.Thr508Ala	missense_variant	10/11		XP_016876167.1
KLHL1	XM_017020679.2	c.1372A>G	p.Thr458Ala	missense_variant	10/11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.2041A>G	p.Thr681Ala	missense_variant	10/11	1	NM_020866.3	ENSP00000367075	P1
KLHL1	ENST00000545028.2	c.1858A>G	p.Thr620Ala	missense_variant	9/10	2		ENSP00000439602

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Sep 06, 2022

The c.2041A>G (p.T681A) alteration is located in exon 10 (coding exon 10) of the KLHL1 gene. This alteration results from a A to G substitution at nucleotide position 2041, causing the threonine (T) at amino acid position 681 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	0.18
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.063	T;T
Polyphen		0.90	P;.
Vest4		0.77
MutPred		0.50		Gain of catalytic residue at A684 (P = 0.0344);.;
MVP		0.92
MPC		0.32
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.18
gMVP		0.40

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: chr13-70281903;