rs113986680

Variant names:

• chr14-45185264-A-C
• rs113986680
• NM_020937.4:c.4563A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020937.4(FANCM):​c.4563A>C​(p.Glu1521Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,604,676 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1521V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0870
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007030189).
• BP6: Variant 14-45185264-A-C is Benign according to our data. Variant chr14-45185264-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00356 (542/152312) while in subpopulation AFR AF = 0.0123 (513/41572). AF 95% confidence interval is 0.0115. There are 5 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.4563A>C	p.Glu1521Asp	missense	Exon 18 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.4485A>C	p.Glu1495Asp	missense	Exon 17 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.4563A>C	p.Glu1521Asp	missense	Exon 18 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.4485A>C	p.Glu1495Asp	missense	Exon 17 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.4356A>C	p.Glu1452Asp	missense	Exon 17 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 538 AN: 152196 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00100 AC: 249 AN: 248982 AF XY: 0.000714

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000553

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000389 AC: 565 AN: 1452364 Hom.: 5 Cov.: 27 AF XY: 0.000307 AC XY: 222 AN XY: 722880

African (AFR) AF: 0.0142 AC: 471 AN: 33202

American (AMR) AF: 0.000695 AC: 31 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5728

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1104486

Other (OTH) AF: 0.000884 AC: 53 AN: 59978

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152312 Hom.: 5 Cov.: 32 AF XY: 0.00348 AC XY: 259 AN XY: 74490

African (AFR) AF: 0.0123 AC: 513 AN: 41572

American (AMR) AF: 0.00124 AC: 19 AN: 15294

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00152 Hom.: 4

Bravo AF: 0.00402

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	FANCM-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.087
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.10	T
Sift4G	Benign	0.29	T
Polyphen		0.79	P
Vest4		0.30
MutPred		0.15		Gain of relative solvent accessibility (P = 0.1571)
MVP		0.68
MPC		0.17
ClinPred		0.027	T
GERP RS		0.56
Varity_R		0.065
gMVP		0.10
Mutation Taster		=98/2	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: rs113986680; hg19: chr14-45654467;