rs147863385

Variant names:

• chr3-42686722-C-T
• rs147863385
• NM_152393.4:c.1104C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-42686722-C-T
• chr3-42686722-C-G

Variant summary

Our verdict is Benign. The variant received -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
• 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=-0.43).
• BP6: Variant 3-42686722-C-T is Benign according to our data. Variant chr3-42686722-C-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.1104C>T	p.Phe368Phe	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.1104C>T	p.Phe368Phe	synonymous	Exon 1 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1104C>T	p.Phe368Phe	synonymous	Exon 1 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1104C>T	p.Phe368Phe	synonymous	Exon 1 of 6	ENSP00000612408.1

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

GnomAD2 exomes AF: 0.00627 AC: 1569 AN: 250244 AF XY: 0.00632

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 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

African (AFR) AF: 0.00131 AC: 44 AN: 33472

American (AMR) AF: 0.00380 AC: 170 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00192 AC: 166 AN: 86246

European-Finnish (FIN) AF: 0.00576 AC: 303 AN: 52648

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0102 AC: 11347 AN: 1111930

Other (OTH) AF: 0.00790 AC: 477 AN: 60376

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

African (AFR) AF: 0.00183 AC: 76 AN: 41578

American (AMR) AF: 0.00791 AC: 121 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 688 AN: 68034

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00819 Hom.: 4

Bravo AF: 0.00629

EpiCase AF: 0.00905

EpiControl AF: 0.00954

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		0.41
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs147863385; hg19: chr3-42728214;