chr11-22623867-G-A

Variant names:

• chr11-22623867-G-A
• rs450946
• NM_022725.4:c.*819C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022725.4(FANCF):​c.*819C>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 0.973 in 188,056 control chromosomes in the GnomAD database, including 89,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71557 hom., cov: 30)
  • Exomes 𝑓: 0.99 (17571 hom.)
• Consequence: FANCF NM_022725.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.840
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-22623867-G-A is Benign according to our data. Variant chr11-22623867-G-A is described in ClinVar as [Benign]. Clinvar id is 304185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.*819C>T		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.*819C>T		3_prime_UTR_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3

Frequencies

GnomAD3 genomes AF: 0.969 AC: 147329 AN: 152078 Hom.: 71517 Cov.: 30

Gnomad AFR AF: 0.903

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.972

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.977

GnomAD4 exome AF: 0.990 AC: 35493 AN: 35860 Hom.: 17571 Cov.: 0 AF XY: 0.990 AC XY: 16523 AN XY: 16698

African (AFR) AF: 0.916 AC: 1314 AN: 1434

American (AMR) AF: 0.994 AC: 787 AN: 792

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2336 AN: 2336

East Asian (EAS) AF: 0.971 AC: 6316 AN: 6502

South Asian (SAS) AF: 0.971 AC: 297 AN: 306

European-Finnish (FIN) AF: 1.00 AC: 22 AN: 22

Middle Eastern (MID) AF: 1.00 AC: 222 AN: 222

European-Non Finnish (NFE) AF: 1.00 AC: 21333 AN: 21334

Other (OTH) AF: 0.984 AC: 2866 AN: 2912

GnomAD4 genome AF: 0.969 AC: 147426 AN: 152196 Hom.: 71557 Cov.: 30 AF XY: 0.969 AC XY: 72116 AN XY: 74414

African (AFR) AF: 0.903 AC: 37453 AN: 41480

American (AMR) AF: 0.992 AC: 15163 AN: 15292

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.921 AC: 4760 AN: 5170

South Asian (SAS) AF: 0.972 AC: 4686 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.993 AC: 290 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 68010 AN: 68026

Other (OTH) AF: 0.976 AC: 2058 AN: 2108

Alfa AF: 0.983 Hom.: 8569

Bravo AF: 0.966

Asia WGS AF: 0.951 AC: 3308 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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	-0.82
CADD	Benign	1.0
DANN	Benign	0.92
PhyloP100		-0.84
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: rs450946; hg19: chr11-22645413;