chr16-87755258-G-A

Variant names:

• chr16-87755258-G-A
• rs2303771
• NM_017566.4:c.305C>T
• KLHDC4 p.Thr102Ile

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 46 publications found

Genes affected

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

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017566.4. 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
	KLHDC4	NM_017566.4	MANE Select	c.305C>T	p.Thr102Ile	missense	Exon 4 of 12	NP_060036.2
	KLHDC4	NM_001184856.2		c.305C>T	p.Thr102Ile	missense	Exon 4 of 11	NP_001171785.1	Q8TBB5-3
	KLHDC4	NM_001184854.2		c.134C>T	p.Thr45Ile	missense	Exon 2 of 10	NP_001171783.1	Q8TBB5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC4	ENST00000270583.10	TSL:1 MANE Select	c.305C>T	p.Thr102Ile	missense	Exon 4 of 12	ENSP00000270583.4	Q8TBB5-1
	KLHDC4	ENST00000347925.9	TSL:1	c.305C>T	p.Thr102Ile	missense	Exon 4 of 11	ENSP00000325717.5	Q8TBB5-3
	KLHDC4	ENST00000353170.9	TSL:1	c.134C>T	p.Thr45Ile	missense	Exon 2 of 10	ENSP00000262530.5	Q8TBB5-2

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

GnomAD2 exomes AF: 0.392 AC: 98365 AN: 250844 AF XY: 0.394

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 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

African (AFR) AF: 0.374 AC: 12382 AN: 33078

American (AMR) AF: 0.476 AC: 21215 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7924 AN: 26018

East Asian (EAS) AF: 0.365 AC: 14461 AN: 39592

South Asian (SAS) AF: 0.530 AC: 45511 AN: 85914

European-Finnish (FIN) AF: 0.364 AC: 19387 AN: 53236

Middle Eastern (MID) AF: 0.327 AC: 1881 AN: 5746

European-Non Finnish (NFE) AF: 0.346 AC: 379989 AN: 1097432

Other (OTH) AF: 0.361 AC: 21608 AN: 59808

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

African (AFR) AF: 0.386 AC: 15980 AN: 41422

American (AMR) AF: 0.425 AC: 6488 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1076 AN: 3466

East Asian (EAS) AF: 0.365 AC: 1887 AN: 5166

South Asian (SAS) AF: 0.531 AC: 2560 AN: 4820

European-Finnish (FIN) AF: 0.356 AC: 3756 AN: 10546

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23792 AN: 67950

Other (OTH) AF: 0.337 AC: 710 AN: 2108

Alfa AF: 0.358 Hom.: 30854

Bravo AF: 0.373

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 v4.9

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
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.00030	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.6	N
PhyloP100		4.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.29
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2303771;

hg19: chr16-87788864;

COSMIC: COSV54508181;

COSMIC: COSV54508181;