Genetic Variant NM_032120.4:c.27G>A (chr7-92528840-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_032120.4(RBM48):c.27G>A(p.Gly9Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,614,042 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 172 hom. )

Consequence

RBM48
NM_032120.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.908

Publications

5 publications found

Variant links:

Genes affected

RBM48 (HGNC:21785): (RNA binding motif protein 48) Predicted to enable RNA binding activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RBM48 links:

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

PEX1 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 1A (Zellweger)
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, Myriad Women’s Health
Heimler syndrome 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
peroxisome biogenesis disorder 1B
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 7-92528840-G-A is Benign according to our data. Variant chr7-92528840-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1211594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.908 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1541/152312) while in subpopulation NFE AF = 0.0162 (1101/68024). AF 95% confidence interval is 0.0154. There are 11 homozygotes in GnomAd4. There are 677 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032120.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBM48	NM_032120.4	MANE Select	c.27G>A	p.Gly9Gly	synonymous	Exon 1 of 5	NP_115496.2	Q5RL73-1
RBM48	NM_001363366.1		c.27G>A	p.Gly9Gly	synonymous	Exon 1 of 6	NP_001350295.1
RBM48	NM_001363367.1		c.-663G>A		5_prime_UTR	Exon 1 of 5	NP_001350296.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBM48	ENST00000265732.10	TSL:1 MANE Select	c.27G>A	p.Gly9Gly	synonymous	Exon 1 of 5	ENSP00000265732.5	Q5RL73-1
RBM48	ENST00000481551.5	TSL:1	c.27G>A	p.Gly9Gly	synonymous	Exon 1 of 4	ENSP00000419242.1	Q5RL73-2
RBM48	ENST00000496410.1	TSL:3	c.-407G>A		5_prime_UTR	Exon 1 of 3	ENSP00000418333.1	C9J787

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1540

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00613

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0106

AC:

2626

AN:

248856

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.00273

Gnomad AMR exome

AF:

0.00757

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00693

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0136

AC:

19882

AN:

1461730

Hom.:

172

Cov.:

AF XY:

0.0133

AC XY:

9644

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33474

American (AMR)

AF:

0.00776

AC:

347

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

295

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00218

AC:

188

AN:

86240

European-Finnish (FIN)

AF:

0.00766

AC:

409

AN:

53416

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0160

AC:

17751

AN:

1111898

Other (OTH)

AF:

0.0119

AC:

721

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

923

1846

2769

3692

4615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.0101

AC:

1541

AN:

152312

Hom.:

Cov.:

AF XY:

0.00909

AC XY:

677

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00298

AC:

124

AN:

41572

American (AMR)

AF:

0.0104

AC:

159

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00394

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00613

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1101

AN:

68024

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

162

242

323

404

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:

0.0142

Hom.:

Bravo

AF:

0.0103

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0179

EpiControl

AF:

0.0188

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.30

(source)

DANN

Benign

0.86

PhyloP100

-0.91

PromoterAI

-0.0021

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over