11-22624770-C-A

Variant names:

• chr11-22624770-C-A
• rs587778343
• NM_022725.4:c.1041G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022725.4(FANCF):​c.1041G>T​(p.Trp347Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W347L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCF NM_022725.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.70
• Publications: 7 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.1041G>T	p.Trp347Cys	missense_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.1041G>T	p.Trp347Cys	missense_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-13	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.72		Loss of stability (P = 0.1522);
MVP		0.91
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.80
Mutation Taster		=26/74	disease causing

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: rs587778343; hg19: chr11-22646316; COSMIC: COSV59416052; COSMIC: COSV59416052;