4-39086721-A-C

Position:

• chr4-39086721-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_015990.5(KLHL5):​c.1107A>C​(p.Ala369=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,611,014 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (116 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (104 hom.)
• Consequence: KLHL5 NM_015990.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33

Genes affected

KLHL5 (HGNC:6356): (kelch like family member 5) Predicted to enable actin binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL5	NM_015990.5	c.1107A>C	p.Ala369=	synonymous_variant	5/11	ENST00000504108.7
LOC105374418	XR_925235.4	n.66+9033T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL5	ENST00000504108.7	c.1107A>C	p.Ala369=	synonymous_variant	5/11	2	NM_015990.5	A1
	ENST00000668468.1	n.270-17587T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3093 AN: 152106 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00555 AC: 1393 AN: 250842 Hom.: 46 AF XY: 0.00397 AC XY: 538 AN XY: 135556

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00220 AC: 3205 AN: 1458790 Hom.: 104 Cov.: 29 AF XY: 0.00192 AC XY: 1397 AN XY: 725926

Gnomad4 AFR exome AF: 0.0743

Gnomad4 AMR exome AF: 0.00486

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000793

Gnomad4 OTH exome AF: 0.00609

GnomAD4 genome AF: 0.0205 AC: 3124 AN: 152224 Hom.: 116 Cov.: 32 AF XY: 0.0196 AC XY: 1461 AN XY: 74436

Gnomad4 AFR AF: 0.0707

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0114 Hom.: 27

Bravo AF: 0.0229

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.1
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35141484; hg19: chr4-39088341;