Genetic Variant RHBDD1:c.656-72T>C (chr2-226908750-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001167608.3(RHBDD1):c.656-72T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,019,964 control chromosomes in the GnomAD database, including 92,446 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 0.44 ( 14575 hom., cov: 31)

Exomes 𝑓: 0.42 ( 77871 hom. )

Consequence

RHBDD1
NM_001167608.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.616

Publications

24 publications found

Variant links:

Genes affected

RHBDD1 (HGNC:23081): (rhomboid domain containing 1) Enables serine-type endopeptidase activity. Involved in several processes, including cellular response to unfolded protein; membrane protein proteolysis; and positive regulation of protein catabolic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

RHBDD1 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=-0.9).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167608.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RHBDD1	NM_001167608.3	MANE Select	c.656-72T>C	intron	N/A	NP_001161080.1	Q8TEB9-1
RHBDD1	NM_001349069.2		c.656-72T>C	intron	N/A	NP_001335998.1	Q8TEB9-1
RHBDD1	NM_001349071.2		c.656-72T>C	intron	N/A	NP_001336000.1	Q8TEB9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RHBDD1	ENST00000392062.7	TSL:5 MANE Select	c.656-72T>C	intron	N/A	ENSP00000375914.2	Q8TEB9-1
RHBDD1	ENST00000341329.7	TSL:1	c.656-72T>C	intron	N/A	ENSP00000344779.3	Q8TEB9-1
RHBDD1	ENST00000491490.5	TSL:1	n.276-72T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.435

AC:

66072

AN:

151812

Hom.:

14548

Cov.:

show subpopulations

Gnomad AFR

AF:

0.490

Gnomad AMI

AF:

0.383

Gnomad AMR

AF:

0.442

Gnomad ASJ

AF:

0.406

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.473

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.400

Gnomad OTH

AF:

0.396

GnomAD4 exome

AF:

0.419

AC:

363881

AN:

868032

Hom.:

77871

Cov.:

AF XY:

0.420

AC XY:

191811

AN XY:

456562

show subpopulations

African (AFR)

AF:

0.479

AC:

10170

AN:

21242

American (AMR)

AF:

0.515

AC:

21087

AN:

40922

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

9051

AN:

21852

East Asian (EAS)

AF:

0.389

AC:

14329

AN:

36878

South Asian (SAS)

AF:

0.505

AC:

36945

AN:

73180

European-Finnish (FIN)

AF:

0.477

AC:

25194

AN:

52800

Middle Eastern (MID)

AF:

0.333

AC:

1510

AN:

4534

European-Non Finnish (NFE)

AF:

0.397

AC:

228973

AN:

576092

Other (OTH)

AF:

0.410

AC:

16622

AN:

40532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

10605

21210

31815

42420

53025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4796

9592

14388

19184

23980

<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:

0.435

AC:

66148

AN:

151932

Hom.:

14575

Cov.:

AF XY:

0.437

AC XY:

32487

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.490

AC:

20285

AN:

41398

American (AMR)

AF:

0.443

AC:

6772

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.406

AC:

1408

AN:

3470

East Asian (EAS)

AF:

0.353

AC:

1824

AN:

5174

South Asian (SAS)

AF:

0.501

AC:

2402

AN:

4798

European-Finnish (FIN)

AF:

0.473

AC:

4988

AN:

10548

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.400

AC:

27198

AN:

67938

Other (OTH)

AF:

0.391

AC:

826

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1899

3798

5697

7596

9495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

626

1252

1878

2504

3130

<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:

0.410

Hom.:

26503

Bravo

AF:

0.436

Asia WGS

AF:

0.442

AC:

1539

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.6

(source)

DANN

Benign

0.57

PhyloP100

-0.62

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over