dbSNP rs2295982: KLHDC3:c.-59-35C>T (chr6-43017099-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_057161.4(KLHDC3):c.-59-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,440,342 control chromosomes in the GnomAD database, including 292 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. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0047 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 257 hom. )

Consequence

KLHDC3
NM_057161.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.313

Publications

1 publications found

Variant links:

Genes affected

KLHDC3 (HGNC:20704): (kelch domain containing 3) The protein encoded by this gene contains six repeated kelch motifs that are structurally similar to recombination activating gene 2, a protein involved in the activation of the V(D)J recombination. In mouse, this gene is found to be expressed specifically in testis. Its expression in pachytene spermatocytes is localized to cytoplasma and meiotic chromatin, suggesting that this gene may be involved in meiotic recombination. [provided by RefSeq, Jun 2012]

KLHDC3 links:

MEA1 (HGNC:6986): (male-enhanced antigen 1) Predicted to be involved in male gonad development. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MEA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC3	NM_057161.4 link	c.-59-35C>T		intron_variant	Intron 1 of 10	ENST00000326974.9	NP_476502.1	Q9BQ90

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHDC3	ENST00000326974.9 link	c.-59-35C>T	intron_variant	Intron 1 of 10	1	NM_057161.4	ENSP00000313995.4	Q9BQ90
KLHDC3	ENST00000244670.12 link	c.-345-35C>T	intron_variant	Intron 1 of 9	1		ENSP00000244670.8	F8W6A4
MEA1	ENST00000645375.1 link	c.-316G>A	upstream_gene_variant				ENSP00000493661.1	A0A2R8Y7W8
MEA1	ENST00000645410.1 link	c.-691G>A	upstream_gene_variant				ENSP00000494198.1	A0A2R8Y7W8

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

715

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.113

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00382

GnomAD4 exome

AF:

0.00392

AC:

5053

AN:

1288074

Hom.:

257

Cov.:

AF XY:

0.00374

AC XY:

2392

AN XY:

640030

show subpopulations

African (AFR)

AF:

0.000231

AC:

AN:

30350

American (AMR)

AF:

0.000352

AC:

AN:

39770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21498

East Asian (EAS)

AF:

0.110

AC:

4253

AN:

38764

South Asian (SAS)

AF:

0.00150

AC:

112

AN:

74424

European-Finnish (FIN)

AF:

0.00339

AC:

125

AN:

36842

Middle Eastern (MID)

AF:

0.00131

AC:

AN:

3808

European-Non Finnish (NFE)

AF:

0.000255

AC:

252

AN:

988202

Other (OTH)

AF:

0.00524

AC:

285

AN:

54416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

249

499

748

998

1247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00468

AC:

712

AN:

152268

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

384

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41560

American (AMR)

AF:

0.00216

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.113

AC:

585

AN:

5182

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68000

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00146

Hom.:

Bravo

AF:

0.00472

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

5.2

(source)

DANN

Benign

0.64

PhyloP100

-0.31

BranchPoint Hunter

0.0

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over