14-45136119-G-T

Variant names:

• chr14-45136119-G-T
• rs373268822
• NM_020937.4:c.88G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020937.4(FANCM):​c.88G>T​(p.Glu30*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCM NM_020937.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.571
• Publications: 0 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):

• Fanconi anemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
• 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
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 167 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.88G>T	p.Glu30*	stop_gained	Exon 1 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.88G>T	p.Glu30*	stop_gained	Exon 1 of 22	NP_001295062.1
	FANCM	NM_001308134.2		c.88G>T	p.Glu30*	stop_gained	Exon 1 of 11	NP_001295063.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.88G>T	p.Glu30*	stop_gained	Exon 1 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.88G>T	p.Glu30*	stop_gained	Exon 1 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.88G>T	p.Glu30*	stop_gained	Exon 1 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.20	N
PhyloP100		0.57
Vest4		0.71
GERP RS		2.0
PromoterAI		-0.094	Neutral
Mutation Taster		=7/193	disease causing (fs/PTC)

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: rs373268822; hg19: chr14-45605322;