chr7-23106054-A-G

Variant names:

• chr7-23106054-A-G
• rs781538844
• NM_001031710.3:c.28A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001031710.3(KLHL7):​c.28A>G​(p.Ser10Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,457,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the KLHL7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.907 (above the threshold of 3.09). Trascript score misZ: 5.0301 (above the threshold of 3.09). GenCC associations: The gene is linked to PERCHING syndrome, retinitis pigmentosa 42, cold-induced sweating syndrome, retinitis pigmentosa.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07397926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL7	NM_001031710.3	c.28A>G	p.Ser10Gly	missense_variant	Exon 1 of 11	ENST00000339077.10	NP_001026880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL7	ENST00000339077.10	c.28A>G	p.Ser10Gly	missense_variant	Exon 1 of 11	1	NM_001031710.3	ENSP00000343273.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 240572 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000895

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1457808 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 724724

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000454 AC: 2 AN: 44076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110636

Other (OTH) AF: 0.0000166 AC: 1 AN: 60250

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 10 of the KLHL7 protein (p.Ser10Gly). This variant is present in population databases (rs781538844, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with KLHL7-related conditions. ClinVar contains an entry for this variant (Variation ID: 1357706). 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 tolerated. 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	0.058
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.062
Sift	Uncertain	0.027	D;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.23		Loss of phosphorylation at S10 (P = 0.0054);Loss of phosphorylation at S10 (P = 0.0054);
MVP		0.77
MPC		0.18
ClinPred		0.14	T
GERP RS		2.4
PromoterAI		0.040	Neutral
Varity_R		0.22
gMVP		0.15
Mutation Taster		=78/22	polymorphism

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

LitVar

Other links and lift over

dbSNP: rs781538844; hg19: chr7-23145673;