rs201803784

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020937.4(FANCM):​c.4709G>A​(p.Arg1570His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000822 in 1,582,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.390
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007450044).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANCMNM_020937.4 linkuse as main transcriptc.4709G>A p.Arg1570His missense_variant 19/23 ENST00000267430.10 NP_065988.1 Q8IYD8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANCMENST00000267430.10 linkuse as main transcriptc.4709G>A p.Arg1570His missense_variant 19/231 NM_020937.4 ENSP00000267430.5 Q8IYD8-1

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152022
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00232
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000287
AC:
72
AN:
250470
Hom.:
0
AF XY:
0.000288
AC XY:
39
AN XY:
135456
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00316
Gnomad SAS exome
AF:
0.0000655
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000706
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000741
AC:
106
AN:
1429972
Hom.:
0
Cov.:
25
AF XY:
0.0000771
AC XY:
55
AN XY:
713446
show subpopulations
Gnomad4 AFR exome
AF:
0.0000609
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000386
Gnomad4 EAS exome
AF:
0.00132
Gnomad4 SAS exome
AF:
0.0000468
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000378
Gnomad4 OTH exome
AF:
0.0000843
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00232
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.000144
ExAC
AF:
0.000346
AC:
42
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 23, 2022In 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; This variant is associated with the following publications: (PMID: 32566746) -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submittercurationSema4, Sema4May 29, 2021- -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterresearchCancer Genomics Group, Japanese Foundation For Cancer ResearchMay 01, 2019- -
Fanconi anemia Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -
FANCM-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 23, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
6.6
DANN
Benign
0.92
DEOGEN2
Benign
0.24
T;.;.
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.058
N
LIST_S2
Benign
0.77
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.0075
T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
0.65
N;.;.
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-2.1
N;N;D
REVEL
Benign
0.13
Sift
Benign
0.071
T;T;T
Sift4G
Benign
0.082
T;T;T
Polyphen
0.029
B;.;.
Vest4
0.061
MVP
0.56
MPC
0.11
ClinPred
0.027
T
GERP RS
-1.1
Varity_R
0.043
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs201803784; hg19: chr14-45657020; COSMIC: COSV99950894; API