rs147863385

Positions:

• chr3-42686722-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152393.4(KLHL40):​c.1104C>T​(p.Phe368Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,613,298 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (69 hom.)
• Consequence: KLHL40 NM_152393.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.407

Genes affected

KLHL40 (HGNC:30372): (kelch like family member 40) This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-42686722-C-T is Benign according to our data. Variant chr3-42686722-C-T is described in ClinVar as [Benign]. Clinvar id is 262640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.407 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00632 (962/152328) while in subpopulation NFE AF= 0.0101 (688/68034). AF 95% confidence interval is 0.00949. There are 5 homozygotes in gnomad4. There are 449 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL40	NM_152393.4	c.1104C>T	p.Phe368Phe	synonymous_variant	1/6	ENST00000287777.5	NP_689606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL40	ENST00000287777.5	c.1104C>T	p.Phe368Phe	synonymous_variant	1/6	1	NM_152393.4	ENSP00000287777.4

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00627 AC: 1569 AN: 250244 Hom.: 10 AF XY: 0.00632 AC XY: 856 AN XY: 135508

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00578

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00863 AC: 12603 AN: 1460970 Hom.: 69 Cov.: 34 AF XY: 0.00843 AC XY: 6124 AN XY: 726792

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.00576

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.00632 AC: 962 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00603 AC XY: 449 AN XY: 74474

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00819 Hom.: 4

Bravo AF: 0.00629

EpiCase AF: 0.00905

EpiControl AF: 0.00954

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 25, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KLHL40: BP4, BS1, BS2 -

Nemaline myopathy 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.67

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: rs147863385; hg19: chr3-42728214;