14-45159080-TTATA-TTA

Variant names:

• chr14-45159080-TTA-T
• rs112326758
• NM_020937.4:c.1397-3_1397-2delTA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BA1

The NM_020937.4(FANCM):​c.1397-3_1397-2delTA variant causes a splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,415,016 control chromosomes in the GnomAD database, including 8,448 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.091 (764 hom., cov: 30)
  • Exomes 𝑓: 0.11 (7684 hom.)
• Consequence: FANCM NM_020937.4 splice_acceptor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.918
• Publications: 4 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 -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.030095981 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 0 (no position change), new splice context is: aagtttttatatatatatAGctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 14-45159080-TTA-T is Benign according to our data. Variant chr14-45159080-TTA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261381.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 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.1397-3_1397-2delTA		splice_acceptor splice_region intron	N/A	NP_065988.1
	FANCM	NM_001308133.2		c.1319-3_1319-2delTA		splice_acceptor splice_region intron	N/A	NP_001295062.1
	FANCM	NM_001308134.2		c.1397-3_1397-2delTA		splice_acceptor splice_region intron	N/A	NP_001295063.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.1397-15_1397-14delTA		intron	N/A	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.1319-15_1319-14delTA		intron	N/A	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.1397-15_1397-14delTA		intron	N/A	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13782 AN: 151270 Hom.: 763 Cov.: 30

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.177 AC: 23609 AN: 133184 AF XY: 0.183

Gnomad AFR exome AF: 0.0653

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.185

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.112 AC: 141719 AN: 1263634 Hom.: 7684 AF XY: 0.115 AC XY: 72393 AN XY: 629880

African (AFR) AF: 0.0401 AC: 1099 AN: 27390

American (AMR) AF: 0.147 AC: 5082 AN: 34678

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3310 AN: 22906

East Asian (EAS) AF: 0.131 AC: 4422 AN: 33732

South Asian (SAS) AF: 0.194 AC: 13628 AN: 70426

European-Finnish (FIN) AF: 0.127 AC: 5983 AN: 47112

Middle Eastern (MID) AF: 0.142 AC: 603 AN: 4254

European-Non Finnish (NFE) AF: 0.105 AC: 101529 AN: 970932

Other (OTH) AF: 0.116 AC: 6063 AN: 52204

GnomAD4 genome AF: 0.0911 AC: 13789 AN: 151382 Hom.: 764 Cov.: 30 AF XY: 0.0928 AC XY: 6862 AN XY: 73956

African (AFR) AF: 0.0383 AC: 1583 AN: 41354

American (AMR) AF: 0.113 AC: 1706 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3460

East Asian (EAS) AF: 0.118 AC: 609 AN: 5162

South Asian (SAS) AF: 0.183 AC: 880 AN: 4808

European-Finnish (FIN) AF: 0.109 AC: 1133 AN: 10370

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 290

European-Non Finnish (NFE) AF: 0.103 AC: 6995 AN: 67774

Other (OTH) AF: 0.116 AC: 245 AN: 2104

Alfa AF: 0.0762 Hom.: 128

Bravo AF: 0.0893

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)
-	-	1	Premature ovarian failure 15 (1)
-	-	1	Spermatogenic failure 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs112326758; hg19: chr14-45628283;