rs45556032

chr11-22625424-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022725.4(FANCF):c.387C>T(p.Leu129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00927 in 1,614,150 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (83 hom.)
• Consequence: FANCF NM_022725.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.60

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-22625424-G-A is Benign according to our data. Variant chr11-22625424-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22625424-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00728 (1110/152370) while in subpopulation NFE AF= 0.0112 (762/68030). AF 95% confidence interval is 0.0105. There are 5 homozygotes in gnomad4. There are 550 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCF	NM_022725.4	c.387C>T	p.Leu129=	synonymous_variant	1/1	ENST00000327470.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCF	ENST00000327470.6	c.387C>T	p.Leu129=	synonymous_variant	1/1		NM_022725.4	P1

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1110 AN: 152252 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00706 AC: 1764 AN: 249956 Hom.: 9 AF XY: 0.00708 AC XY: 961 AN XY: 135706

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00916

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00901

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00786

GnomAD4 exome AF: 0.00947 AC: 13848 AN: 1461780 Hom.: 83 Cov.: 32 AF XY: 0.00926 AC XY: 6731 AN XY: 727192

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00797

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00815

GnomAD4 genome AF: 0.00728 AC: 1110 AN: 152370 Hom.: 5 Cov.: 33 AF XY: 0.00738 AC XY: 550 AN XY: 74506

Gnomad4 AFR AF: 0.00151

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00925 Hom.: 0

Bravo AF: 0.00642

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FANCF: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	- -

Fanconi anemia complementation group F Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	1.0
Dann	Benign	0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs45556032; hg19: chr11-22646970; COSMIC: COSV59416488; COSMIC: COSV59416488;