chr13-69839156-C-G

Position:

• chr13-69839156-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020866.3(KLHL1):​c.1234G>C​(p.Ala412Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1234G>C	p.Ala412Pro	missense_variant	6/11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1051G>C	p.Ala351Pro	missense_variant	5/10		NP_001273654.1
KLHL1	XM_017020678.3	c.715G>C	p.Ala239Pro	missense_variant	6/11		XP_016876167.1
KLHL1	XM_017020679.2	c.565G>C	p.Ala189Pro	missense_variant	6/11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.1234G>C	p.Ala412Pro	missense_variant	6/11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1051G>C	p.Ala351Pro	missense_variant	5/10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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

Aug 14, 2024

The c.1234G>C (p.A412P) alteration is located in exon 6 (coding exon 6) of the KLHL1 gene. This alteration results from a G to C substitution at nucleotide position 1234, causing the alanine (A) at amino acid position 412 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.54
Sift	Benign	0.047	D;.
Sift4G	Uncertain	0.020	D;D
Polyphen		0.99	D;.
Vest4		0.78
MutPred		0.54		Gain of catalytic residue at P407 (P = 0);.;
MVP		0.94
MPC		0.41
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.80
gMVP		0.65

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: chr13-70413288;