11-22623948-A-C

Variant names:

• chr11-22623948-A-C
• rs76674060
• NM_022725.4:c.*738T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_022725.4(FANCF):​c.*738T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 211,104 control chromosomes in the GnomAD database, including 17 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 0.0085 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: FANCF NM_022725.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.161
• Publications: 1 publications found

Genes affected

FANCF (HGNC:3587): (FA complementation group F) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group F. [provided by RefSeq, Jul 2008]

FANCF Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00846 (1286/152078) while in subpopulation AFR AF = 0.0295 (1224/41454). AF 95% confidence interval is 0.0282. There are 16 homozygotes in GnomAd4. There are 590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.*738T>G		3_prime_UTR_variant	Exon 1 of 1	ENST00000327470.6	NP_073562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCF	ENST00000327470.6	c.*738T>G		3_prime_UTR_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3

Frequencies

GnomAD3 genomes AF: 0.00841 AC: 1278 AN: 151960 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00672

GnomAD4 exome AF: 0.00178 AC: 105 AN: 59026 Hom.: 1 Cov.: 0 AF XY: 0.00159 AC XY: 44 AN XY: 27650

African (AFR) AF: 0.0304 AC: 81 AN: 2662

American (AMR) AF: 0.00117 AC: 2 AN: 1704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3768

East Asian (EAS) AF: 0.00 AC: 0 AN: 8862

South Asian (SAS) AF: 0.00 AC: 0 AN: 518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46

Middle Eastern (MID) AF: 0.00281 AC: 1 AN: 356

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 36228

Other (OTH) AF: 0.00430 AC: 21 AN: 4882

GnomAD4 genome AF: 0.00846 AC: 1286 AN: 152078 Hom.: 16 Cov.: 32 AF XY: 0.00793 AC XY: 590 AN XY: 74360

African (AFR) AF: 0.0295 AC: 1224 AN: 41454

American (AMR) AF: 0.00249 AC: 38 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67982

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00941

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group F Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.72
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

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: rs76674060; hg19: chr11-22645494;