11-61796827-G-T

Variant names:

• chr11-61796827-G-T
• rs4246215
• NM_004111.6:c.*323G>T

Variant summary

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

The NM_004111.6(FEN1):​c.*323G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 301,298 control chromosomes in the GnomAD database, including 18,410 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 0.30 (8648 hom., cov: 32)
  • Exomes 𝑓: 0.34 (9762 hom.)
• Consequence: FEN1 NM_004111.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 168 publications found

Genes affected

FEN1 (HGNC:3650): (flap structure-specific endonuclease 1) The protein encoded by this gene removes 5' overhanging flaps in DNA repair and processes the 5' ends of Okazaki fragments in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. DNA secondary structure can inhibit flap processing at certain trinucleotide repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by the protein encoded by this gene. Therefore, secondary structure can deter the protective function of this protein, leading to site-specific trinucleotide expansions. [provided by RefSeq, Jul 2008]

FADS2 (HGNC:3575): (fatty acid desaturase 2) The protein encoded by this gene is a member of the fatty acid desaturase (FADS) gene family. Desaturase enzymes regulate unsaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEN1	NM_004111.6	c.*323G>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000305885.3	NP_004102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FEN1	ENST00000305885.3	c.*323G>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_004111.6	ENSP00000305480.2
FEN1	ENST00000535307.1	c.457-95G>T		intron_variant	Intron 1 of 1	2		ENSP00000460402.1
FADS2	ENST00000574708.5	n.49+3799G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45062 AN: 152022 Hom.: 8626 Cov.: 32

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.339 AC: 50509 AN: 149158 Hom.: 9762 Cov.: 0 AF XY: 0.326 AC XY: 25423 AN XY: 77996

African (AFR) AF: 0.0672 AC: 244 AN: 3632

American (AMR) AF: 0.582 AC: 2946 AN: 5066

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 1095 AN: 4042

East Asian (EAS) AF: 0.440 AC: 3106 AN: 7052

South Asian (SAS) AF: 0.172 AC: 3225 AN: 18802

European-Finnish (FIN) AF: 0.450 AC: 9338 AN: 20734

Middle Eastern (MID) AF: 0.211 AC: 116 AN: 550

European-Non Finnish (NFE) AF: 0.341 AC: 27868 AN: 81806

Other (OTH) AF: 0.344 AC: 2571 AN: 7474

GnomAD4 genome AF: 0.296 AC: 45095 AN: 152140 Hom.: 8648 Cov.: 32 AF XY: 0.303 AC XY: 22536 AN XY: 74370

African (AFR) AF: 0.0805 AC: 3343 AN: 41544

American (AMR) AF: 0.490 AC: 7486 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3468

East Asian (EAS) AF: 0.553 AC: 2869 AN: 5184

South Asian (SAS) AF: 0.186 AC: 895 AN: 4820

European-Finnish (FIN) AF: 0.449 AC: 4739 AN: 10560

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23689 AN: 67960

Other (OTH) AF: 0.345 AC: 731 AN: 2116

Alfa AF: 0.247 Hom.: 3574

Bravo AF: 0.296

Asia WGS AF: 0.377 AC: 1310 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	16
DANN	Benign	0.82
PhyloP100		1.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
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: rs4246215; hg19: chr11-61564299; COSMIC: COSV57251547; COSMIC: COSV57251547;