rs3744358

Variant names:

• chr17-35009895-T-G
• rs3744358
• NM_001017368.2:c.*2073A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001017368.2(RFFL):​c.*2073A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 152,578 control chromosomes in the GnomAD database, including 5,779 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5766 hom., cov: 32)
  • Exomes 𝑓: 0.27 (13 hom.)
• Consequence: RFFL NM_001017368.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.119
• Publications: 17 publications found

Genes affected

RFFL (HGNC:24821): (ring finger and FYVE like domain containing E3 ubiquitin protein ligase) Enables enzyme binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in cellular protein metabolic process; negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis; and negative regulation of signal transduction. Located in endosome membrane and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RAD51L3-RFFL (HGNC:):

LIG3 (HGNC:6600): (DNA ligase 3) This gene is a member of the DNA ligase family. Each member of this family encodes a protein that catalyzes the joining of DNA ends but they each have a distinct role in DNA metabolism. The protein encoded by this gene is involved in excision repair and is located in both the mitochondria and nucleus, with translation initiation from the upstream start codon allowing for transport to the mitochondria and translation initiation from a downstream start codon allowing for transport to the nucleus. Additionally, alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

LIG3 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 20 (mngie type)

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFFL	NM_001017368.2	c.*2073A>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000394597.7	NP_001017368.1
LIG3	NM_013975.4	c.*5389T>G		downstream_gene_variant		ENST00000378526.9	NP_039269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFFL	ENST00000394597.7	c.*2073A>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_001017368.2	ENSP00000378096.3
RFFL	ENST00000315249.11	c.*2073A>C		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000326170.7
RFFL	ENST00000584655.5	c.*2073A>C		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000463035.1
LIG3	ENST00000378526.9	c.*5389T>G		downstream_gene_variant		1	NM_013975.4	ENSP00000367787.3

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40218 AN: 152026 Hom.: 5766 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.293

GnomAD4 exome AF: 0.267 AC: 116 AN: 434 Hom.: 13 Cov.: 0 AF XY: 0.267 AC XY: 70 AN XY: 262

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.268 AC: 114 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.264 AC: 40228 AN: 152144 Hom.: 5766 Cov.: 32 AF XY: 0.263 AC XY: 19572 AN XY: 74360

African (AFR) AF: 0.168 AC: 6970 AN: 41514

American (AMR) AF: 0.389 AC: 5940 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3472

East Asian (EAS) AF: 0.0957 AC: 496 AN: 5182

South Asian (SAS) AF: 0.249 AC: 1201 AN: 4824

European-Finnish (FIN) AF: 0.258 AC: 2730 AN: 10582

Middle Eastern (MID) AF: 0.277 AC: 81 AN: 292

European-Non Finnish (NFE) AF: 0.311 AC: 21141 AN: 67970

Other (OTH) AF: 0.291 AC: 616 AN: 2116

Alfa AF: 0.296 Hom.: 12621

Bravo AF: 0.272

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.4
DANN	Benign	0.82
PhyloP100		0.12
Mutation Taster		=100/0	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: rs3744358; hg19: chr17-33336914;