13-69882383-A-T

Variant summary

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

The NM_020866.3(KLHL1):c.1127T>A(p.Phe376Tyr) 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: 9.32

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, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL1	NM_020866.3	c.1127T>A	p.Phe376Tyr	missense_variant	5/11	ENST00000377844.9
KLHL1	NM_001286725.2	c.944T>A	p.Phe315Tyr	missense_variant	4/10
KLHL1	XM_017020678.3	c.608T>A	p.Phe203Tyr	missense_variant	5/11
KLHL1	XM_017020679.2	c.458T>A	p.Phe153Tyr	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL1	ENST00000377844.9	c.1127T>A	p.Phe376Tyr	missense_variant	5/11	1	NM_020866.3	P1
KLHL1	ENST00000545028.2	c.944T>A	p.Phe315Tyr	missense_variant	4/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jan 30, 2024

The c.1127T>A (p.F376Y) alteration is located in exon 5 (coding exon 5) of the KLHL1 gene. This alteration results from a T to A substitution at nucleotide position 1127, causing the phenylalanine (F) at amino acid position 376 to be replaced by a tyrosine (Y). 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.46
Sift	Benign	0.056	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.87	P;.
Vest4		0.75
MutPred		0.57		Gain of catalytic residue at I375 (P = 0.0022);.;
MVP		0.67
MPC		0.19
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.28
gMVP		0.51

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: chr13-70456515;