2-110577006-C-A

Variant names:

• chr2-110577006-C-A
• rs761147198
• NM_001123363.4:c.19G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001123363.4(RGPD6):​c.19G>T​(p.Asp7Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 5)
  • Exomes 𝑓: 0.000051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RGPD6 NM_001123363.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

Genes affected

RGPD6 (HGNC:32419): (RANBP2 like and GRIP domain containing 6) Predicted to contribute to GTPase activator activity. Predicted to be involved in NLS-bearing protein import into nucleus. Predicted to be part of nuclear pore. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017768085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD6	NM_001123363.4	c.19G>T	p.Asp7Tyr	missense_variant	Exon 1 of 23	ENST00000329516.8	NP_001116835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD6	ENST00000329516.8	c.19G>T	p.Asp7Tyr	missense_variant	Exon 1 of 23	1	NM_001123363.4	ENSP00000330842.3

Frequencies

GnomAD3 genomes AF: 0.000120 AC: 3 AN: 25012 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00450

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000610 AC: 1 AN: 16388 AF XY: 0.000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000511 AC: 31 AN: 606898 Hom.: 0 Cov.: 9 AF XY: 0.0000711 AC XY: 21 AN XY: 295340

African (AFR) AF: 0.00 AC: 0 AN: 9208

American (AMR) AF: 0.00 AC: 0 AN: 11262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8424

East Asian (EAS) AF: 0.00475 AC: 31 AN: 6528

South Asian (SAS) AF: 0.00 AC: 0 AN: 28246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1458

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 507590

Other (OTH) AF: 0.00 AC: 0 AN: 20372

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000120 AC: 3 AN: 25012 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 12770

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 5368

American (AMR) AF: 0.00 AC: 0 AN: 3542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 808

East Asian (EAS) AF: 0.00450 AC: 3 AN: 666

South Asian (SAS) AF: 0.00 AC: 0 AN: 376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 58

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12512

Other (OTH) AF: 0.00 AC: 0 AN: 350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000716 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19G>T (p.D7Y) alteration is located in exon 2 (coding exon 1) of the RGPD6 gene. This alteration results from a G to T substitution at nucleotide position 19, causing the aspartic acid (D) at amino acid position 7 to be replaced by a tyrosine (Y). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.62
DEOGEN2	Benign	0.075	.;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	.;.;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-0.63	T
PhyloP100		3.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.15
Sift	Benign	0.11	T;T;T
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.26
MutPred		0.23		Loss of disorder (P = 0.0424);Loss of disorder (P = 0.0424);Loss of disorder (P = 0.0424);
MVP		0.29
MPC		1.9
ClinPred		0.19	T
GERP RS		1.0
PromoterAI		0.058	Neutral
gMVP		0.10
Mutation Taster		=99/1	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

Publications

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Other links and lift over

dbSNP: rs761147198; hg19: chr2-111334583;