14-45136054-T-A

Variant summary

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

The NM_020937.4(FANCM):​c.23T>A​(p.Leu8His) 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 1,461,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.41
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.23T>A p.Leu8His missense_variant 1/23 ENST00000267430.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCMENST00000267430.10 linkuse as main transcriptc.23T>A p.Leu8His missense_variant 1/231 NM_020937.4 P1Q8IYD8-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248700
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
135022
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461396
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000825
AC:
1

ClinVar

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

Submissions by phenotype

Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 18, 2023This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 8 of the FANCM protein (p.Leu8His). This variant is present in population databases (rs753737880, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
28
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.47
.;T;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.75
T;T;T
M_CAP
Uncertain
0.088
D
MetaRNN
Uncertain
0.50
D;D;D
MetaSVM
Benign
-0.74
T
MutationAssessor
Uncertain
2.5
M;M;M
MutationTaster
Benign
0.97
D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-5.3
D;D;D
REVEL
Benign
0.21
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.67
MutPred
0.27
Gain of catalytic residue at R6 (P = 0.0111);Gain of catalytic residue at R6 (P = 0.0111);Gain of catalytic residue at R6 (P = 0.0111);
MVP
0.66
MPC
0.53
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.91
gMVP
0.85

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: rs753737880; hg19: chr14-45605257; API