chr16-74630845-T-C

Variant names:

• chr16-74630845-T-C
• rs7193541
• NM_018124.4:c.1690A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018124.4(RFWD3):​c.1690A>G​(p.Ile564Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,613,106 control chromosomes in the GnomAD database, including 133,593 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 (★).

• Frequency:
  • Genomes: 𝑓 0.42 (14042 hom., cov: 32)
  • Exomes 𝑓: 0.40 (119551 hom.)
• Consequence: RFWD3 NM_018124.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57
• Publications: 65 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3153424E-4).
• BP6: Variant 16-74630845-T-C is Benign according to our data. Variant chr16-74630845-T-C is described in ClinVar as Benign. ClinVar VariationId is 2124096.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFWD3	NM_018124.4	c.1690A>G	p.Ile564Val	missense_variant	Exon 10 of 13	ENST00000361070.9	NP_060594.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFWD3	ENST00000361070.9	c.1690A>G	p.Ile564Val	missense_variant	Exon 10 of 13	1	NM_018124.4	ENSP00000354361.4
RFWD3	ENST00000571750.5	c.1690A>G	p.Ile564Val	missense_variant	Exon 11 of 14	2		ENSP00000460049.1
RFWD3	ENST00000575154.1	n.324A>G		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64063 AN: 151860 Hom.: 14033 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.425

GnomAD2 exomes AF: 0.370 AC: 92839 AN: 250638 AF XY: 0.367

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.436

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.399 AC: 583288 AN: 1461126 Hom.: 119551 Cov.: 41 AF XY: 0.394 AC XY: 286659 AN XY: 726858

African (AFR) AF: 0.511 AC: 17078 AN: 33430

American (AMR) AF: 0.249 AC: 11125 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 9185 AN: 26122

East Asian (EAS) AF: 0.371 AC: 14713 AN: 39644

South Asian (SAS) AF: 0.237 AC: 20429 AN: 86188

European-Finnish (FIN) AF: 0.344 AC: 18375 AN: 53400

Middle Eastern (MID) AF: 0.450 AC: 2597 AN: 5766

European-Non Finnish (NFE) AF: 0.419 AC: 465288 AN: 1111560

Other (OTH) AF: 0.406 AC: 24498 AN: 60370

GnomAD4 genome AF: 0.422 AC: 64095 AN: 151980 Hom.: 14042 Cov.: 32 AF XY: 0.414 AC XY: 30753 AN XY: 74266

African (AFR) AF: 0.508 AC: 21037 AN: 41434

American (AMR) AF: 0.329 AC: 5021 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1217 AN: 3472

East Asian (EAS) AF: 0.418 AC: 2155 AN: 5158

South Asian (SAS) AF: 0.243 AC: 1172 AN: 4824

European-Finnish (FIN) AF: 0.349 AC: 3677 AN: 10546

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28292 AN: 67962

Other (OTH) AF: 0.426 AC: 897 AN: 2108

Alfa AF: 0.416 Hom.: 64535

Bravo AF: 0.426

TwinsUK AF: 0.419 AC: 1553

ALSPAC AF: 0.418 AC: 1610

ESP6500AA AF: 0.510 AC: 2240

ESP6500EA AF: 0.423 AC: 3637

ExAC AF: 0.381 AC: 46229

Asia WGS AF: 0.358 AC: 1244 AN: 3478

EpiCase AF: 0.411

EpiControl AF: 0.422

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.1
DANN	Benign	0.92
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	.;T
MetaRNN	Benign	0.00023	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.23	N;N
PhyloP100		1.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.19	N;.
REVEL	Benign	0.037
Sift	Benign	0.47	T;.
Sift4G	Benign	0.57	T;T
Polyphen		0.0080	B;B
Vest4		0.061
ClinPred		0.0011	T
GERP RS		3.4
Varity_R		0.048
gMVP		0.14
Mutation Taster		=96/4	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: rs7193541; hg19: chr16-74664743; COSMIC: COSV63097488;