rs752364451

chr14-45154705-C-Gchr14-45154705-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020937.4(FANCM):c.1192C>G(p.Arg398Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.1192C>G	p.Arg398Gly	missense_variant	7/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.1192C>G	p.Arg398Gly	missense_variant	7/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1438788 Hom.: 0 Cov.: 27 AF XY: 0.00000279 AC XY: 2 AN XY: 716280

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000678

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2022

Not 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	0.67
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.9	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.23	T;D;D
Polyphen		0.51	P;P;.
Vest4		0.84
MutPred		0.51		Gain of catalytic residue at L403 (P = 0.0014);Gain of catalytic residue at L403 (P = 0.0014);.;
MVP		0.60
MPC		0.49
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.64
gMVP		0.55

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

Other links and lift over

dbSNP: rs752364451; hg19: chr14-45623908;