rs4888262

chr16-74636560-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018124.4(RFWD3):c.1212G>A(p.Thr404=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,611,680 control chromosomes in the GnomAD database, including 229,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27489 hom., cov: 31)
  • Exomes 𝑓: 0.52 (202218 hom.)
• Consequence: RFWD3 NM_018124.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.458

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-74636560-C-T is Benign according to our data. Variant chr16-74636560-C-T is described in ClinVar as [Benign]. Clinvar id is 1327953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.458 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFWD3	NM_018124.4	c.1212G>A	p.Thr404=	synonymous_variant	8/13	ENST00000361070.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFWD3	ENST00000361070.9	c.1212G>A	p.Thr404=	synonymous_variant	8/13	1	NM_018124.4	P1
RFWD3	ENST00000571750.5	c.1212G>A	p.Thr404=	synonymous_variant	9/14	2		P1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89303 AN: 151882 Hom.: 27453 Cov.: 31

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.588

GnomAD3 exomes AF: 0.538 AC: 134863 AN: 250466 Hom.: 37850 AF XY: 0.540 AC XY: 73174 AN XY: 135414

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.756

Gnomad SAS exome AF: 0.604

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.521 AC: 760547 AN: 1459680 Hom.: 202218 Cov.: 38 AF XY: 0.523 AC XY: 379750 AN XY: 726126

Gnomad4 AFR exome AF: 0.776

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.478

Gnomad4 EAS exome AF: 0.747

Gnomad4 SAS exome AF: 0.598

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.545

GnomAD4 genome AF: 0.588 AC: 89389 AN: 152000 Hom.: 27489 Cov.: 31 AF XY: 0.586 AC XY: 43560 AN XY: 74294

Gnomad4 AFR AF: 0.769

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.479

Gnomad4 EAS AF: 0.753

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.456

Gnomad4 NFE AF: 0.510

Gnomad4 OTH AF: 0.588

Alfa AF: 0.528 Hom.: 50404

Bravo AF: 0.597

Asia WGS AF: 0.695 AC: 2413 AN: 3478

EpiCase AF: 0.507

EpiControl AF: 0.521

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia, complementation group W Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

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
BayesDel_noAF	Benign	-0.67
Cadd	Benign	2.5
Dann	Benign	0.34

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: rs4888262; hg19: chr16-74670458; COSMIC: COSV63098019; COSMIC: COSV63098019;