NM_020937.4:c.4387-1012G>A

Variant names:

• chr14-45182762-G-A
• rs11845507
• NM_020937.4:c.4387-1012G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020937.4(FANCM):​c.4387-1012G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,048 control chromosomes in the GnomAD database, including 5,332 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (5332 hom., cov: 32)
• Consequence: FANCM NM_020937.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.830
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

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.4387-1012G>A		intron	N/A	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.4309-1012G>A		intron	N/A	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.4387-1012G>A		intron	N/A	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.4309-1012G>A		intron	N/A	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.4180-1012G>A		intron	N/A	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33410 AN: 151930 Hom.: 5295 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.213

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.220 AC: 33507 AN: 152048 Hom.: 5332 Cov.: 32 AF XY: 0.218 AC XY: 16195 AN XY: 74334

African (AFR) AF: 0.453 AC: 18783 AN: 41460

American (AMR) AF: 0.178 AC: 2724 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3468

East Asian (EAS) AF: 0.135 AC: 697 AN: 5170

South Asian (SAS) AF: 0.187 AC: 901 AN: 4816

European-Finnish (FIN) AF: 0.108 AC: 1143 AN: 10568

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.119 AC: 8121 AN: 67986

Other (OTH) AF: 0.212 AC: 447 AN: 2112

Alfa AF: 0.153 Hom.: 3133

Bravo AF: 0.234

Asia WGS AF: 0.176 AC: 613 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.88
DANN	Benign	0.29
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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: rs11845507; hg19: chr14-45651965;