X-153944417-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002910.6(RENBP):c.29A>G(p.Asp10Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,205,468 control chromosomes in the GnomAD database, including 3 homozygotes. There are 758 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 44 hem., cov: 24)
  • Exomes 𝑓: 0.0022 (3 hom. 714 hem.)
• Consequence: RENBP NM_002910.6 missense, splice_region
• Scores: Splicing: ADA: 0.004905
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:2
• Conservation: PhyloP100: 0.674

Genes affected

RENBP (HGNC:9959): (renin binding protein) The gene product inhibits renin activity by forming a dimer with renin, a complex known as high molecular weight renin. The encoded protein contains a leucine zipper domain, which is essential for its dimerization with renin. The gene product can catalyze the interconversion of N-acetylglucosamine to N-acetylmannosamine, indicating that it is a GlcNAc 2-epimerase. Transcript variants utilizing alternative promoters have been described in the literature. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009738386).
• BS2: High Hemizygotes in GnomAd at 44 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RENBP	NM_002910.6	c.29A>G	p.Asp10Gly	missense_variant, splice_region_variant	2/11	ENST00000393700.8
RENBP	XM_017029698.2	c.-2A>G		splice_region_variant, 5_prime_UTR_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RENBP	ENST00000393700.8	c.29A>G	p.Asp10Gly	missense_variant, splice_region_variant	2/11	1	NM_002910.6	P1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 168 AN: 111698 Hom.: 0 Cov.: 24 AF XY: 0.00130 AC XY: 44 AN XY: 33886

Gnomad AFR AF: 0.000522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000816

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.00104 AC: 190 AN: 182549 Hom.: 0 AF XY: 0.000905 AC XY: 61 AN XY: 67435

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.00218 AC: 2386 AN: 1093716 Hom.: 3 Cov.: 30 AF XY: 0.00199 AC XY: 714 AN XY: 359326

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000696

Gnomad4 NFE exome AF: 0.00269

Gnomad4 OTH exome AF: 0.00196

GnomAD4 genome AF: 0.00150 AC: 168 AN: 111752 Hom.: 0 Cov.: 24 AF XY: 0.00130 AC XY: 44 AN XY: 33950

Gnomad4 AFR AF: 0.000521

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000816

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.00183 Hom.: 66

Bravo AF: 0.00136

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00282 AC: 19

ExAC AF: 0.00103 AC: 125

EpiCase AF: 0.00164

EpiControl AF: 0.00178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 16, 2021	The c.29A>G (p.D10G) alteration is located in exon 2 (coding exon 2) of the RENBP gene. This alteration results from a A to G substitution at nucleotide position 29, causing the aspartic acid (D) at amino acid position 10 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.87	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.025
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.0	B;.
Vest4		0.18
MVP		0.13
MPC		0.60
ClinPred		0.055	T
GERP RS		3.1
Varity_R		0.26
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0049
dbscSNV1_RF	Benign	0.020
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

LitVar

Other links and lift over

dbSNP: rs138548063; hg19: chrX-153209869; COSMIC: COSV60072187; COSMIC: COSV60072187;