NM_018124.4:c.1212G>A

Variant names:

• chr16-74636560-C-T
• rs4888262
• NM_018124.4:c.1212G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018124.4(RFWD3):​c.1212G>A​(p.Thr404Thr) 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:3
• Conservation: PhyloP100: -0.458
• Publications: 60 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Tourette syndrome

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFWD3	NM_018124.4	MANE Select	c.1212G>A	p.Thr404Thr	synonymous	Exon 8 of 13	NP_060594.3
	RFWD3	NM_001370534.1		c.1212G>A	p.Thr404Thr	synonymous	Exon 8 of 13	NP_001357463.1	Q6PCD5
	RFWD3	NM_001370535.1		c.1212G>A	p.Thr404Thr	synonymous	Exon 9 of 14	NP_001357464.1	Q6PCD5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFWD3	ENST00000361070.9	TSL:1 MANE Select	c.1212G>A	p.Thr404Thr	synonymous	Exon 8 of 13	ENSP00000354361.4	Q6PCD5
	RFWD3	ENST00000571750.5	TSL:2	c.1212G>A	p.Thr404Thr	synonymous	Exon 9 of 14	ENSP00000460049.1	Q6PCD5
	RFWD3	ENST00000938436.1		c.1212G>A	p.Thr404Thr	synonymous	Exon 10 of 15	ENSP00000608495.1

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

GnomAD2 exomes AF: 0.538 AC: 134863 AN: 250466 AF XY: 0.540

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 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

African (AFR) AF: 0.776 AC: 25963 AN: 33442

American (AMR) AF: 0.429 AC: 19168 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 12469 AN: 26112

East Asian (EAS) AF: 0.747 AC: 29652 AN: 39686

South Asian (SAS) AF: 0.598 AC: 51527 AN: 86148

European-Finnish (FIN) AF: 0.445 AC: 23782 AN: 53398

Middle Eastern (MID) AF: 0.579 AC: 3138 AN: 5422

European-Non Finnish (NFE) AF: 0.506 AC: 562020 AN: 1110554

Other (OTH) AF: 0.545 AC: 32828 AN: 60284

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

African (AFR) AF: 0.769 AC: 31865 AN: 41460

American (AMR) AF: 0.501 AC: 7642 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1660 AN: 3468

East Asian (EAS) AF: 0.753 AC: 3895 AN: 5172

South Asian (SAS) AF: 0.618 AC: 2975 AN: 4812

European-Finnish (FIN) AF: 0.456 AC: 4808 AN: 10546

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34632 AN: 67966

Other (OTH) AF: 0.588 AC: 1243 AN: 2114

Alfa AF: 0.535 Hom.: 100109

Bravo AF: 0.597

Asia WGS AF: 0.695 AC: 2413 AN: 3478

EpiCase AF: 0.507

EpiControl AF: 0.521

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fanconi anemia, complementation group W (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.5
DANN	Benign	0.34
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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