rs45547534

Variant names:

• chr14-45137184-A-G
• rs45547534
• NM_020937.4:c.624A>G

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.624A>G​(p.Ile208Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,613,676 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (11 hom., cov: 32)
  • Exomes 𝑓: 0.015 (183 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0190
• Publications: 14 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=0.0072793067).
• BP6: Variant 14-45137184-A-G is Benign according to our data. Variant chr14-45137184-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1601/152300) while in subpopulation NFE AF = 0.0165 (1121/68024). AF 95% confidence interval is 0.0157. There are 11 homozygotes in GnomAd4. There are 707 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.624A>G	p.Ile208Met	missense	Exon 2 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.624A>G	p.Ile208Met	missense	Exon 2 of 22	NP_001295062.1	Q8IYD8-3
	FANCM	NM_001308134.2		c.624A>G	p.Ile208Met	missense	Exon 2 of 11	NP_001295063.1	Q8IYD8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.624A>G	p.Ile208Met	missense	Exon 2 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.624A>G	p.Ile208Met	missense	Exon 2 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.624A>G	p.Ile208Met	missense	Exon 2 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1601 AN: 152182 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0102 AC: 2566 AN: 251204 AF XY: 0.0106

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00656

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.0146 AC: 21277 AN: 1461376 Hom.: 183 Cov.: 31 AF XY: 0.0145 AC XY: 10548 AN XY: 727010

African (AFR) AF: 0.00242 AC: 81 AN: 33476

American (AMR) AF: 0.00707 AC: 316 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.0108 AC: 935 AN: 86254

European-Finnish (FIN) AF: 0.00593 AC: 315 AN: 53144

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5766

European-Non Finnish (NFE) AF: 0.0170 AC: 18877 AN: 1111830

Other (OTH) AF: 0.0110 AC: 662 AN: 60380

GnomAD4 genome AF: 0.0105 AC: 1601 AN: 152300 Hom.: 11 Cov.: 32 AF XY: 0.00949 AC XY: 707 AN XY: 74474

African (AFR) AF: 0.00296 AC: 123 AN: 41552

American (AMR) AF: 0.0134 AC: 205 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4832

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0165 AC: 1121 AN: 68024

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0134 Hom.: 58

Bravo AF: 0.0106

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0107 AC: 1296

Asia WGS AF: 0.00433 AC: 17 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0152

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Fanconi anemia (1)
-	-	1	Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.019
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.90	P
Vest4		0.33
MPC		0.45
ClinPred		0.062	T
GERP RS		0.0078
Varity_R		0.55
gMVP		0.55
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs45547534; hg19: chr14-45606387; COSMIC: COSV53531926; COSMIC: COSV53531926;