rs2303771

chr16-87755258-G-Achr16-87755258-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017566.4(KLHDC4):c.305C>T(p.Thr102Ile) variant causes a missense change. The variant allele was found at a frequency of 0.364 in 1,597,314 control chromosomes in the GnomAD database, including 109,493 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (10758 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98735 hom.)
• Consequence: KLHDC4 NM_017566.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.37

Genes affected

KLHDC4 (HGNC:25272): (kelch domain containing 4)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9858947E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHDC4	NM_017566.4	c.305C>T	p.Thr102Ile	missense_variant	4/12	ENST00000270583.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHDC4	ENST00000270583.10	c.305C>T	p.Thr102Ile	missense_variant	4/12	1	NM_017566.4	P1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56498 AN: 151824 Hom.: 10751 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.392 AC: 98365 AN: 250844 Hom.: 20214 AF XY: 0.394 AC XY: 53461 AN XY: 135600

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.385

Gnomad SAS exome AF: 0.522

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.363 AC: 524358 AN: 1445372 Hom.: 98735 Cov.: 30 AF XY: 0.368 AC XY: 264715 AN XY: 719744

Gnomad4 AFR exome AF: 0.374

Gnomad4 AMR exome AF: 0.476

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.365

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.364

Gnomad4 NFE exome AF: 0.346

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.372 AC: 56539 AN: 151942 Hom.: 10758 Cov.: 32 AF XY: 0.377 AC XY: 28006 AN XY: 74258

Gnomad4 AFR AF: 0.386

Gnomad4 AMR AF: 0.425

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.531

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.337

Alfa AF: 0.354 Hom.: 21087

Bravo AF: 0.373

TwinsUK AF: 0.356 AC: 1319

ALSPAC AF: 0.354 AC: 1363

ESP6500AA AF: 0.379 AC: 1665

ESP6500EA AF: 0.352 AC: 3025

ExAC AF: 0.392 AC: 47578

Asia WGS AF: 0.415 AC: 1443 AN: 3478

EpiCase AF: 0.338

EpiControl AF: 0.335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	7.8
Dann	Benign	0.069
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	T;T;T;T
MetaRNN	Benign	0.00030	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	3.7	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;.
Polyphen		0.0010	B;B;B;.
Vest4		0.20
MPC		0.013
ClinPred		0.0079	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2303771; hg19: chr16-87788864; COSMIC: COSV54508181; COSMIC: COSV54508181;