NM_018124.4:c.269C>A

Variant names:

• chr16-74661181-G-T
• rs8058922
• NM_018124.4:c.269C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018124.4(RFWD3):​c.269C>A​(p.Thr90Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,614,032 control chromosomes in the GnomAD database, including 383,635 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T90A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (41146 hom., cov: 33)
  • Exomes 𝑓: 0.68 (342489 hom.)
• Consequence: RFWD3 NM_018124.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.40
• Publications: 48 publications found

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]

RFWD3 Gene-Disease associations (from GenCC):

• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia, complementation group W

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.974846E-7).
• BP6: Variant 16-74661181-G-T is Benign according to our data. Variant chr16-74661181-G-T is described in ClinVar as Benign. ClinVar VariationId is 1327954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFWD3	NM_018124.4	MANE Select	c.269C>A	p.Thr90Asn	missense	Exon 2 of 13	NP_060594.3
	RFWD3	NM_001370537.1		c.-740C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_001357466.1
	RFWD3	NM_001370539.1		c.-363C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001357468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFWD3	ENST00000361070.9	TSL:1 MANE Select	c.269C>A	p.Thr90Asn	missense	Exon 2 of 13	ENSP00000354361.4
	RFWD3	ENST00000571750.5	TSL:2	c.269C>A	p.Thr90Asn	missense	Exon 3 of 14	ENSP00000460049.1
	RFWD3	ENST00000572990.5	TSL:4	c.269C>A	p.Thr90Asn	missense	Exon 3 of 3	ENSP00000459899.1

Frequencies

GnomAD3 genomes AF: 0.730 AC: 111077 AN: 152070 Hom.: 41105 Cov.: 33

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.723

GnomAD2 exomes AF: 0.712 AC: 179034 AN: 251426 AF XY: 0.709

Gnomad AFR exome AF: 0.843

Gnomad AMR exome AF: 0.780

Gnomad ASJ exome AF: 0.571

Gnomad EAS exome AF: 0.814

Gnomad FIN exome AF: 0.643

Gnomad NFE exome AF: 0.665

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.682 AC: 997263 AN: 1461844 Hom.: 342489 Cov.: 73 AF XY: 0.684 AC XY: 497315 AN XY: 727224

African (AFR) AF: 0.846 AC: 28327 AN: 33480

American (AMR) AF: 0.774 AC: 34619 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 15147 AN: 26136

East Asian (EAS) AF: 0.806 AC: 31982 AN: 39700

South Asian (SAS) AF: 0.778 AC: 67065 AN: 86256

European-Finnish (FIN) AF: 0.644 AC: 34392 AN: 53392

Middle Eastern (MID) AF: 0.674 AC: 3890 AN: 5768

European-Non Finnish (NFE) AF: 0.666 AC: 740233 AN: 1111992

Other (OTH) AF: 0.689 AC: 41608 AN: 60396

GnomAD4 genome AF: 0.731 AC: 111178 AN: 152188 Hom.: 41146 Cov.: 33 AF XY: 0.733 AC XY: 54514 AN XY: 74392

African (AFR) AF: 0.843 AC: 35011 AN: 41540

American (AMR) AF: 0.750 AC: 11469 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 1998 AN: 3468

East Asian (EAS) AF: 0.812 AC: 4202 AN: 5172

South Asian (SAS) AF: 0.803 AC: 3873 AN: 4826

European-Finnish (FIN) AF: 0.640 AC: 6773 AN: 10582

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45444 AN: 67998

Other (OTH) AF: 0.725 AC: 1529 AN: 2110

Alfa AF: 0.685 Hom.: 153075

Bravo AF: 0.741

TwinsUK AF: 0.660 AC: 2448

ALSPAC AF: 0.679 AC: 2615

ESP6500AA AF: 0.829 AC: 3645

ESP6500EA AF: 0.671 AC: 5773

ExAC AF: 0.714 AC: 86665

Asia WGS AF: 0.814 AC: 2828 AN: 3478

EpiCase AF: 0.659

EpiControl AF: 0.666

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia, complementation group W Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0020
DANN	Benign	0.13
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	8.0e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-2.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.93	N
REVEL	Benign	0.012
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0080
ClinPred		0.019	T
GERP RS		-9.5
Varity_R		0.053
gMVP		0.067
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8058922; hg19: chr16-74695079; COSMIC: COSV107456470; COSMIC: COSV107456470;