chr14-45188806-C-A

Position:

• chr14-45188806-C-A

Variant summary

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

The NM_020937.4(FANCM):​c.4784C>A​(p.Pro1595His) variant causes a missense change. The variant allele was found at a frequency of 0.0000055 in 1,455,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.75

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]

FANCM (HGNC:):

ACMG classification

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	Protein	UniProt
FANCM	NM_020937.4	c.4784C>A	p.Pro1595His	missense_variant	20/23	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10	c.4784C>A	p.Pro1595His	missense_variant	20/23	1	NM_020937.4	ENSP00000267430.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249438 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135076

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455852 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2024

The p.P1595H variant (also known as c.4784C>A), located in coding exon 20 of the FANCM gene, results from a C to A substitution at nucleotide position 4784. The proline at codon 1595 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2023

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1595 of the FANCM protein (p.Pro1595His). This variant is present in population databases (rs750818919, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. ClinVar contains an entry for this variant (Variation ID: 456272). 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	0.63
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	2.9	M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.70
MutPred		0.42		Loss of helix (P = 0.0068);.;.;
MVP		0.94
MPC		0.49
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.43

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

Other links and lift over

dbSNP: rs750818919; hg19: chr14-45658009;