chr7-23106081-G-C

Position:

• chr7-23106081-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001031710.3(KLHL7):​c.55G>C​(p.Ala19Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

Genes affected

KLHL7 (HGNC:15646): (kelch like family member 7) This gene encodes a BTB-Kelch-related protein. The encoded protein may be involved in protein degradation. Mutations in this gene have been associated with retinitis pigmentosa 42. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KLHL7. . Gene score misZ 3.907 (greater than the threshold 3.09). Trascript score misZ 5.0301 (greater than threshold 3.09). GenCC has associacion of gene with PERCHING syndrome, retinitis pigmentosa 42, cold-induced sweating syndrome, retinitis pigmentosa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL7	NM_001031710.3	c.55G>C	p.Ala19Pro	missense_variant	1/11	ENST00000339077.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL7	ENST00000339077.10	c.55G>C	p.Ala19Pro	missense_variant	1/11	1	NM_001031710.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456754 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

May 23, 2023

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 19 of the KLHL7 protein (p.Ala19Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KLHL7-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.070	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.031	D;T
Polyphen		0.0	B;B
Vest4		0.59
MutPred		0.41		Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);
MVP		0.73
MPC		0.50
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.37
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: chr7-23145700;