chr16-74661182-T-A

Variant names:

• chr16-74661182-T-A
• NM_018124.4:c.268A>T
• RFWD3 p.Thr90Ser

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018124.4(RFWD3):​c.268A>T​(p.Thr90Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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. T90N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFWD3 NM_018124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028135061).

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.268A>T	p.Thr90Ser	missense	Exon 2 of 13	NP_060594.3
	RFWD3	NM_001370534.1		c.268A>T	p.Thr90Ser	missense	Exon 2 of 13	NP_001357463.1	Q6PCD5
	RFWD3	NM_001370535.1		c.268A>T	p.Thr90Ser	missense	Exon 3 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.268A>T	p.Thr90Ser	missense	Exon 2 of 13	ENSP00000354361.4	Q6PCD5
	RFWD3	ENST00000571750.5	TSL:2	c.268A>T	p.Thr90Ser	missense	Exon 3 of 14	ENSP00000460049.1	Q6PCD5
	RFWD3	ENST00000938436.1		c.268A>T	p.Thr90Ser	missense	Exon 4 of 15	ENSP00000608495.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.1
DANN	Benign	0.34
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.087	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.34
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.0080
Sift	Benign	0.44	T
Sift4G	Benign	0.89	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.080

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-74695080;