Genetic Variant NM_178491.4:c.262-38A>G (chr20-44341158-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_178491.4(R3HDML):c.262-38A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,537,372 control chromosomes in the GnomAD database, including 27,719 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 0.18 ( 2765 hom., cov: 33)

Exomes 𝑓: 0.18 ( 24954 hom. )

Consequence

R3HDML
NM_178491.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.77

Publications

14 publications found

Variant links:

Genes affected

R3HDML (HGNC:16249): (R3H domain containing like) Predicted to enable peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

R3HDML links:

R3HDML-AS1 (HGNC:55830): (R3HDML antisense RNA 1)

R3HDML-AS1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDML	NM_178491.4 link	c.262-38A>G		intron_variant	Intron 1 of 4	ENST00000217043.4	NP_848586.1	Q9H3Y0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDML	ENST00000217043.4 link	c.262-38A>G		intron_variant	Intron 1 of 4	1	NM_178491.4	ENSP00000217043.3		Q9H3Y0
R3HDML-AS1	ENST00000735551.1 link	n.601-2098T>C		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26830

AN:

152112

Hom.:

2746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.208

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.170

GnomAD2 exomes

AF:

0.218

AC:

52111

AN:

239062

AF XY:

0.213

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.401

Gnomad ASJ exome

AF:

0.202

Gnomad EAS exome

AF:

0.380

Gnomad FIN exome

AF:

0.122

Gnomad NFE exome

AF:

0.161

Gnomad OTH exome

AF:

0.202

GnomAD4 exome

AF:

0.178

AC:

247030

AN:

1385142

Hom.:

24954

Cov.:

AF XY:

0.180

AC XY:

123735

AN XY:

688460

show subpopulations

African (AFR)

AF:

0.122

AC:

3916

AN:

32022

American (AMR)

AF:

0.383

AC:

16283

AN:

42494

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

4906

AN:

24610

East Asian (EAS)

AF:

0.387

AC:

15076

AN:

38940

South Asian (SAS)

AF:

0.242

AC:

20066

AN:

82852

European-Finnish (FIN)

AF:

0.122

AC:

6422

AN:

52786

Middle Eastern (MID)

AF:

0.166

AC:

856

AN:

5154

European-Non Finnish (NFE)

AF:

0.161

AC:

169051

AN:

1048814

Other (OTH)

AF:

0.182

AC:

10454

AN:

57470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

9696

19392

29089

38785

48481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.177

AC:

26878

AN:

152230

Hom.:

2765

Cov.:

AF XY:

0.180

AC XY:

13383

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.133

AC:

5522

AN:

41576

American (AMR)

AF:

0.297

AC:

4531

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

723

AN:

3472

East Asian (EAS)

AF:

0.373

AC:

1920

AN:

5146

South Asian (SAS)

AF:

0.261

AC:

1262

AN:

4828

European-Finnish (FIN)

AF:

0.118

AC:

1253

AN:

10608

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.163

AC:

11098

AN:

68012

Other (OTH)

AF:

0.175

AC:

368

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1151

2302

3452

4603

5754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.156

Hom.:

1137

Bravo

AF:

0.187

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.17

(source)

DANN

Benign

0.71

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_178491.4:c.262-38A>G

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