16-74628505-A-T

Position:

• chr16-74628505-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_018124.4(RFWD3):​c.1916T>A​(p.Ile639Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFWD3 NM_018124.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.61

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-74628505-A-T is Pathogenic according to our data. Variant chr16-74628505-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 446412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-74628505-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFWD3	NM_018124.4	c.1916T>A	p.Ile639Lys	missense_variant	11/13	ENST00000361070.9	NP_060594.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFWD3	ENST00000361070.9	c.1916T>A	p.Ile639Lys	missense_variant	11/13	1	NM_018124.4	ENSP00000354361.4
RFWD3	ENST00000571750.5	c.1916T>A	p.Ile639Lys	missense_variant	12/14	2		ENSP00000460049.1
RFWD3	ENST00000575154.1	n.*3T>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Fanconi anemia, complementation group W Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 28, 2017

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Sep 08, 2017

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	.;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		0.85	P;P
Vest4		0.69
MutPred		0.61		Gain of methylation at I639 (P = 0.0055);Gain of methylation at I639 (P = 0.0055);
MVP		0.43
ClinPred		0.86	D
GERP RS		2.0
Varity_R		0.53
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555524842; hg19: chr16-74662403;