13-69707678-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020866.3(KLHL1):c.2134A>G(p.Thr712Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16160485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL1	NM_020866.3	c.2134A>G	p.Thr712Ala	missense_variant	10/11	ENST00000377844.9
KLHL1	NM_001286725.2	c.1951A>G	p.Thr651Ala	missense_variant	9/10
KLHL1	XM_017020678.3	c.1615A>G	p.Thr539Ala	missense_variant	10/11
KLHL1	XM_017020679.2	c.1465A>G	p.Thr489Ala	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL1	ENST00000377844.9	c.2134A>G	p.Thr712Ala	missense_variant	10/11	1	NM_020866.3	P1
KLHL1	ENST00000545028.2	c.1951A>G	p.Thr651Ala	missense_variant	9/10	2

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

KLHL1: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.020	N;.
MutationTaster	Benign	0.72	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.16
Sift	Benign	0.36	T;.
Sift4G	Benign	0.42	T;T
Polyphen		0.0020	B;.
Vest4		0.29
MutPred		0.40		Gain of catalytic residue at Q711 (P = 0.0021);.;
MVP		0.77
MPC		0.068
ClinPred		0.14	T
GERP RS		3.9
Varity_R		0.088
gMVP		0.46

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: chr13-70281810; COSMIC: COSV64767972;