Genetic Variant NM_022725.4:c.349C>G (chr11-22625462-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_022725.4(FANCF):c.349C>G(p.Pro117Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P117L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

FANCF
NM_022725.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.53

Publications

7 publications found

Variant links:

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 links:

GAS2 (HGNC:4167): (growth arrest specific 2) The protein encoded by this gene is a caspase-3 substrate that plays a role in regulating microfilament and cell shape changes during apoptosis. It can also modulate cell susceptibility to p53-dependent apoptosis by inhibiting calpain activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2017]

GAS2 Gene-Disease associations (from GenCC):

hearing loss disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hearing loss, autosomal recessive 125
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

GAS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2934304).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022725.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCF	NM_022725.4	MANE Select	c.349C>G	p.Pro117Ala	missense	Exon 1 of 1	NP_073562.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCF	ENST00000327470.6	TSL:6 MANE Select	c.349C>G	p.Pro117Ala	missense	Exon 1 of 1	ENSP00000330875.3
GAS2	ENST00000528582.5	TSL:3	c.-372G>C		upstream_gene	N/A	ENSP00000432584.1
GAS2	ENST00000648096.1		n.-47G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.56

M_CAP

Benign

0.018

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.5

PhyloP100

3.5

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.071

Sift

Benign

0.042

Sift4G

Pathogenic

0.0

Polyphen

0.95

Vest4

0.16

MutPred

0.36

Gain of helix (P = 0.0078)

MVP

0.59

MPC

0.85

ClinPred

0.83

GERP RS

4.3

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.12

gMVP

0.10

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over