rs147327994

chr19-48450437-G-Achr19-48450437-G-C

Variant summary

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

The NM_031485.4(GRWD1):c.593G>A(p.Arg198Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GRWD1 NM_031485.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.17

Genes affected

GRWD1 (HGNC:21270): (glutamate rich WD repeat containing 1) This gene encodes a glutamate-rich protein that contains five WD-repeat motifs. The encoded protein may play a critical role in ribosome biogenesis and may also play a role in histone methylation through interactions with CUL4-DDB1 ubiquitin E3 ligase. [provided by RefSeq, Feb 2012]

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=0.022213042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRWD1	NM_031485.4	c.593G>A	p.Arg198Gln	missense_variant	4/7	ENST00000253237.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRWD1	ENST00000253237.10	c.593G>A	p.Arg198Gln	missense_variant	4/7	1	NM_031485.4	P1
GRWD1	ENST00000598711.1	c.284G>A	p.Arg95Gln	missense_variant	4/6	3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251366 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135868

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1461800 Hom.: 0 Cov.: 33 AF XY: 0.000116 AC XY: 84 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74452

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.593G>A (p.R198Q) alteration is located in exon 4 (coding exon 4) of the GRWD1 gene. This alteration results from a G to A substitution at nucleotide position 593, causing the arginine (R) at amino acid position 198 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.39	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.54	N;.
REVEL	Benign	0.053
Sift	Benign	0.38	T;.
Sift4G	Benign	0.54	T;T
Polyphen		0.0	B;.
Vest4		0.15
MVP		0.77
MPC		0.39
ClinPred		0.026	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs147327994; hg19: chr19-48953694; COSMIC: COSV53521013; COSMIC: COSV53521013;