16-74623954-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018124.4(RFWD3):c.2299A>G(p.Met767Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,614,118 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (4 hom.)
• Consequence: RFWD3 NM_018124.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.460

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00809747).
• BP6: Variant 16-74623954-T-C is Benign according to our data. Variant chr16-74623954-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2064152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFWD3	NM_018124.4	c.2299A>G	p.Met767Val	missense_variant	13/13	ENST00000361070.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFWD3	ENST00000361070.9	c.2299A>G	p.Met767Val	missense_variant	13/13	1	NM_018124.4	P1
RFWD3	ENST00000571750.5	c.2299A>G	p.Met767Val	missense_variant	14/14	2		P1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000708 AC: 178 AN: 251400 Hom.: 2 AF XY: 0.000898 AC XY: 122 AN XY: 135862

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000714 AC: 1044 AN: 1461872 Hom.: 4 Cov.: 31 AF XY: 0.000781 AC XY: 568 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000705

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74442

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000613 Hom.: 0

Bravo AF: 0.000620

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000741 AC: 90

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00124

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RFWD3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	9.4
Dann	Benign	0.68
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.48	N
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.022
Sift	Benign	0.26	T;.
Sift4G	Benign	0.58	T;T
Polyphen		0.0	B;B
Vest4		0.053
MVP		0.25
ClinPred		0.013	T
GERP RS		1.9
Varity_R		0.070
gMVP		0.46

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: rs146574678; hg19: chr16-74657852;