rs7193541

Positions:

• chr16-74630845-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018124.4(RFWD3):​c.1690A>G​(p.Ile564Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,613,106 control chromosomes in the GnomAD database, including 133,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (14042 hom., cov: 32)
  • Exomes 𝑓: 0.40 (119551 hom.)
• Consequence: RFWD3 NM_018124.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57

Genes affected

RFWD3 (HGNC:25539): (ring finger and WD repeat domain 3) Enables MDM2/MDM4 family protein binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in several processes, including DNA metabolic process; regulation of cell cycle phase transition; and response to ionizing radiation. Located in nucleoplasm and site of DNA damage. Colocalizes with site of double-strand break. Implicated in Fanconi anemia. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3153424E-4).
• BP6: Variant 16-74630845-T-C is Benign according to our data. Variant chr16-74630845-T-C is described in ClinVar as [Benign]. Clinvar id is 2124096.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFWD3	NM_018124.4	c.1690A>G	p.Ile564Val	missense_variant	10/13	ENST00000361070.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFWD3	ENST00000361070.9	c.1690A>G	p.Ile564Val	missense_variant	10/13	1	NM_018124.4	P1
RFWD3	ENST00000571750.5	c.1690A>G	p.Ile564Val	missense_variant	11/14	2		P1
RFWD3	ENST00000575154.1	n.324A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64063 AN: 151860 Hom.: 14033 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.370 AC: 92839 AN: 250638 Hom.: 18411 AF XY: 0.367 AC XY: 49768 AN XY: 135466

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.436

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.399 AC: 583288 AN: 1461126 Hom.: 119551 Cov.: 41 AF XY: 0.394 AC XY: 286659 AN XY: 726858

Gnomad4 AFR exome AF: 0.511

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.371

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.419

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.422 AC: 64095 AN: 151980 Hom.: 14042 Cov.: 32 AF XY: 0.414 AC XY: 30753 AN XY: 74266

Gnomad4 AFR AF: 0.508

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.418

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.426

Alfa AF: 0.415 Hom.: 35064

Bravo AF: 0.426

TwinsUK AF: 0.419 AC: 1553

ALSPAC AF: 0.418 AC: 1610

ESP6500AA AF: 0.510 AC: 2240

ESP6500EA AF: 0.423 AC: 3637

ExAC AF: 0.381 AC: 46229

Asia WGS AF: 0.358 AC: 1244 AN: 3478

EpiCase AF: 0.411

EpiControl AF: 0.422

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.1
DANN	Benign	0.92
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.83	D
MetaRNN	Benign	0.00023	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.23	N;N
MutationTaster	Benign	0.092	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.19	N;.
REVEL	Benign	0.037
Sift	Benign	0.47	T;.
Sift4G	Benign	0.57	T;T
Polyphen		0.0080	B;B
Vest4		0.061
ClinPred		0.0011	T
GERP RS		3.4
Varity_R		0.048
gMVP		0.14

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: rs7193541; hg19: chr16-74664743; COSMIC: COSV63097488;