14-45136057-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020937.4(FANCM):ā€‹c.26T>Gā€‹(p.Phe9Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.47
Variant links:
Genes affected
FANCM (HGNC:23168): (FA complementation group M) 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 M. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCMNM_020937.4 linkuse as main transcriptc.26T>G p.Phe9Cys missense_variant 1/23 ENST00000267430.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCMENST00000267430.10 linkuse as main transcriptc.26T>G p.Phe9Cys missense_variant 1/231 NM_020937.4 P1Q8IYD8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461436
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727020
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 25, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
.;T;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.82
T;T;T
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.46
T;T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Uncertain
2.5
M;M;M
MutationTaster
Benign
0.54
N;N;N
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.5
D;D;D
REVEL
Benign
0.20
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.015
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.62
MutPred
0.31
Gain of catalytic residue at L8 (P = 0.0075);Gain of catalytic residue at L8 (P = 0.0075);Gain of catalytic residue at L8 (P = 0.0075);
MVP
0.59
MPC
0.56
ClinPred
0.99
D
GERP RS
3.5
Varity_R
0.83
gMVP
0.61

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1248796174; hg19: chr14-45605260; API