rs200360968

Variant names:

• chr14-45181685-C-T
• rs200360968
• NM_020937.4:c.4366C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_020937.4(FANCM):​c.4366C>T​(p.Arg1456Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,608,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1456L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.694
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• FANCM Fanconi-like genomic instability disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, ClinGen
• spermatogenic failure 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06035438).
• BP6: Variant 14-45181685-C-T is Benign according to our data. Variant chr14-45181685-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 313218.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020937.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.4366C>T	p.Arg1456Cys	missense	Exon 16 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.4288C>T	p.Arg1430Cys	missense	Exon 15 of 22	NP_001295062.1	Q8IYD8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.4366C>T	p.Arg1456Cys	missense	Exon 16 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.4288C>T	p.Arg1430Cys	missense	Exon 15 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.4159C>T	p.Arg1387Cys	missense	Exon 15 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000229 AC: 57 AN: 249256 AF XY: 0.000252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000461

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000325 AC: 474 AN: 1456646 Hom.: 0 Cov.: 29 AF XY: 0.000332 AC XY: 241 AN XY: 724976

African (AFR) AF: 0.0000300 AC: 1 AN: 33378

American (AMR) AF: 0.000202 AC: 9 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5672

European-Non Finnish (NFE) AF: 0.000392 AC: 434 AN: 1107916

Other (OTH) AF: 0.000282 AC: 17 AN: 60180

GnomAD4 genome AF: 0.000257 AC: 39 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74232

African (AFR) AF: 0.0000242 AC: 1 AN: 41382

American (AMR) AF: 0.000262 AC: 4 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 67994

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000709

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	1	-	Fanconi anemia (1)
-	-	1	Hereditary cancer (1)
-	1	-	Spermatogenic failure 28;C4748170:Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.69
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.076
Sift	Benign	0.097	T
Sift4G	Benign	0.092	T
Polyphen		0.032	B
Vest4		0.33
MVP		0.43
MPC		0.13
ClinPred		0.064	T
GERP RS		2.3
Varity_R		0.13
gMVP		0.22
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs200360968; hg19: chr14-45650888;