7-92528821-C-T

Variant names:

• chr7-92528821-C-T
• rs115296343
• NM_032120.4:c.8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001363367.1(RBM48):​c.-682C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,860 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (12 hom.)
• Consequence: RBM48 NM_001363367.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.227
• Publications: 3 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042303503).
• BP6: Variant 7-92528821-C-T is Benign according to our data. Variant chr7-92528821-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 776237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00736 (1121/152288) while in subpopulation AFR AF = 0.0256 (1064/41546). AF 95% confidence interval is 0.0243. There are 16 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363367.1. 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
	RBM48	NM_032120.4	MANE Select	c.8C>T	p.Ser3Leu	missense	Exon 1 of 5	NP_115496.2	Q5RL73-1
	RBM48	NM_001363367.1		c.-682C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001350296.1
	RBM48	NM_001363366.1		c.8C>T	p.Ser3Leu	missense	Exon 1 of 6	NP_001350295.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM48	ENST00000265732.10	TSL:1 MANE Select	c.8C>T	p.Ser3Leu	missense	Exon 1 of 5	ENSP00000265732.5	Q5RL73-1
	RBM48	ENST00000481551.5	TSL:1	c.8C>T	p.Ser3Leu	missense	Exon 1 of 4	ENSP00000419242.1	Q5RL73-2
	RBM48	ENST00000496410.1	TSL:3	c.-426C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000418333.1	C9J787

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152170 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00173 AC: 431 AN: 248726 AF XY: 0.00126

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000726 AC: 1061 AN: 1461572 Hom.: 12 Cov.: 31 AF XY: 0.000593 AC XY: 431 AN XY: 727074

African (AFR) AF: 0.0264 AC: 882 AN: 33464

American (AMR) AF: 0.00123 AC: 55 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111802

Other (OTH) AF: 0.00176 AC: 106 AN: 60382

GnomAD4 genome AF: 0.00736 AC: 1121 AN: 152288 Hom.: 16 Cov.: 32 AF XY: 0.00712 AC XY: 530 AN XY: 74478

African (AFR) AF: 0.0256 AC: 1064 AN: 41546

American (AMR) AF: 0.00255 AC: 39 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00277 Hom.: 7

Bravo AF: 0.00836

ESP6500AA AF: 0.0239 AC: 94

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00209 AC: 252

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.23
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.027
Sift	Benign	0.030	D
Sift4G	Benign	0.090	T
Polyphen		0.14	B
Vest4		0.13
MVP		0.74
MPC		0.19
ClinPred		0.054	T
GERP RS		2.8
PromoterAI		-0.19	Neutral
Varity_R		0.11
gMVP		0.61
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs115296343; hg19: chr7-92158135;