3-42686671-C-T

Variant names:

• chr3-42686671-C-T
• rs61736693
• NM_152393.4:c.1053C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_152393.4(KLHL40):​c.1053C>T​(p.His351His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,613,878 control chromosomes in the GnomAD database, including 474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (257 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (217 hom.)
• Consequence: KLHL40 NM_152393.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.928
• Publications: 1 publications found

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]

KLHL40 Gene-Disease associations (from GenCC):

• nemaline myopathy 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-42686671-C-T is Benign according to our data. Variant chr3-42686671-C-T is described in ClinVar as Benign. ClinVar VariationId is 262639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.928 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152393.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	NM_152393.4	MANE Select	c.1053C>T	p.His351His	synonymous	Exon 1 of 6	NP_689606.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	ENST00000287777.5	TSL:1 MANE Select	c.1053C>T	p.His351His	synonymous	Exon 1 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1053C>T	p.His351His	synonymous	Exon 1 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1053C>T	p.His351His	synonymous	Exon 1 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4854 AN: 152196 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.00920 AC: 2313 AN: 251334 AF XY: 0.00664

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00361 AC: 5270 AN: 1461564 Hom.: 217 Cov.: 34 AF XY: 0.00316 AC XY: 2294 AN XY: 727088

African (AFR) AF: 0.112 AC: 3758 AN: 33480

American (AMR) AF: 0.00948 AC: 424 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00140 AC: 121 AN: 86258

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 53130

Middle Eastern (MID) AF: 0.00745 AC: 43 AN: 5768

European-Non Finnish (NFE) AF: 0.000416 AC: 463 AN: 1111982

Other (OTH) AF: 0.00748 AC: 452 AN: 60388

GnomAD4 genome AF: 0.0319 AC: 4855 AN: 152314 Hom.: 257 Cov.: 32 AF XY: 0.0311 AC XY: 2314 AN XY: 74490

African (AFR) AF: 0.110 AC: 4564 AN: 41558

American (AMR) AF: 0.0125 AC: 191 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68028

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0296 Hom.: 173

Bravo AF: 0.0365

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Nemaline myopathy 8 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.6
DANN	Benign	0.56
PhyloP100		-0.93
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61736693; hg19: chr3-42728163; COSMIC: COSV106376366;