20-62410934-T-C

Position:

• chr20-62410934-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080833.3(RBBP8NL):​c.1939A>G​(p.Arg647Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: RBBP8NL NM_080833.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.159

Genes affected

RBBP8NL (HGNC:16144): (RBBP8 N-terminal like) Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066646725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBBP8NL	NM_080833.3	c.1939A>G	p.Arg647Gly	missense_variant	14/14	ENST00000252998.2	NP_543023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBBP8NL	ENST00000252998.2	c.1939A>G	p.Arg647Gly	missense_variant	14/14	2	NM_080833.3	ENSP00000252998.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250160 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461372 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

The c.1939A>G (p.R647G) alteration is located in exon 14 (coding exon 13) of the RBBP8NL gene. This alteration results from a A to G substitution at nucleotide position 1939, causing the arginine (R) at amino acid position 647 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.9
DANN	Benign	0.89
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.066
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.30	T
Polyphen		0.90	P
Vest4		0.11
MutPred		0.13		Gain of relative solvent accessibility (P = 0.0098);
MVP		0.10
MPC		0.12
ClinPred		0.11	T
GERP RS		-1.7
Varity_R		0.10
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs749530415; hg19: chr20-60985990;