chr14-45194625-G-A

Variant names:

• chr14-45194625-G-A
• rs7141145
• NM_020937.4:c.5341-1547G>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.5341-1547G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 151,886 control chromosomes in the GnomAD database, including 7,304 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 0.25 (7304 hom., cov: 32)
• Consequence: FANCM NM_020937.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.138
• 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):

• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4	c.5341-1547G>A		intron_variant	Intron 20 of 22	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10	c.5341-1547G>A		intron_variant	Intron 20 of 22	1	NM_020937.4	ENSP00000267430.5

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37354 AN: 151768 Hom.: 7266 Cov.: 32

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.247 AC: 37451 AN: 151886 Hom.: 7304 Cov.: 32 AF XY: 0.244 AC XY: 18079 AN XY: 74244

African (AFR) AF: 0.545 AC: 22532 AN: 41374

American (AMR) AF: 0.189 AC: 2879 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3470

East Asian (EAS) AF: 0.136 AC: 701 AN: 5172

South Asian (SAS) AF: 0.187 AC: 902 AN: 4818

European-Finnish (FIN) AF: 0.108 AC: 1141 AN: 10526

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8110 AN: 67954

Other (OTH) AF: 0.234 AC: 494 AN: 2112

Alfa AF: 0.234 Hom.: 1264

Bravo AF: 0.264

Asia WGS AF: 0.179 AC: 624 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.93
DANN	Benign	0.27
PhyloP100		-0.14
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: rs7141145; hg19: chr14-45663828;