13-69740514-T-A

Variant names:

• chr13-69740514-T-A
• NM_020866.3:c.1682A>T

Variant summary

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

The NM_020866.3(KLHL1):​c.1682A>T​(p.His561Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,580 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.94

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, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1682A>T	p.His561Leu	missense_variant	Exon 8 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1499A>T	p.His500Leu	missense_variant	Exon 7 of 10		NP_001273654.1
KLHL1	XM_017020678.3	c.1163A>T	p.His388Leu	missense_variant	Exon 8 of 11		XP_016876167.1
KLHL1	XM_017020679.2	c.1013A>T	p.His338Leu	missense_variant	Exon 8 of 11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.1682A>T	p.His561Leu	missense_variant	Exon 8 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1499A>T	p.His500Leu	missense_variant	Exon 7 of 10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460580 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.85	L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.3	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.067	T;T
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.57		Gain of catalytic residue at V558 (P = 0);.;
MVP		0.95
MPC		0.41
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.80
gMVP		0.73

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: chr13-70314646;