16-74623954-T-G

Variant names:

• chr16-74623954-T-G
• rs146574678
• NM_018124.4:c.2299A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018124.4(RFWD3):​c.2299A>C​(p.Met767Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M767V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RFWD3 NM_018124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.460
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107029855).

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.2299A>C	p.Met767Leu	missense	Exon 13 of 13	NP_060594.3
	RFWD3	NM_001370534.1		c.2299A>C	p.Met767Leu	missense	Exon 13 of 13	NP_001357463.1	Q6PCD5
	RFWD3	NM_001370535.1		c.2299A>C	p.Met767Leu	missense	Exon 14 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.2299A>C	p.Met767Leu	missense	Exon 13 of 13	ENSP00000354361.4	Q6PCD5
	RFWD3	ENST00000571750.5	TSL:2	c.2299A>C	p.Met767Leu	missense	Exon 14 of 14	ENSP00000460049.1	Q6PCD5
	RFWD3	ENST00000938436.1		c.2299A>C	p.Met767Leu	missense	Exon 15 of 15	ENSP00000608495.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.64
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.46
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.019
Sift	Benign	0.30	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.39		Loss of helix (P = 0.0138)
MVP		0.30
ClinPred		0.051	T
GERP RS		1.9
Varity_R		0.072
gMVP		0.42

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: rs146574678; hg19: chr16-74657852;