rs61753893

Variant names:

• chr14-45167125-A-G
• rs61753893
• NM_020937.4:c.1964A>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.1964A>G​(p.Asn655Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,416 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.016 (248 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.410
• Publications: 12 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=0.002967447).
• BP6: Variant 14-45167125-A-G is Benign according to our data. Variant chr14-45167125-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241315.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 = 0.0107 (1626/152324) while in subpopulation NFE AF = 0.0182 (1236/68036). AF 95% confidence interval is 0.0173. There are 17 homozygotes in GnomAd4. There are 684 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.1964A>G	p.Asn655Ser	missense	Exon 11 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.1886A>G	p.Asn629Ser	missense	Exon 10 of 22	NP_001295062.1	Q8IYD8-3
	FANCM	NM_001308134.2		c.1964A>G	p.Asn655Ser	missense	Exon 11 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.1964A>G	p.Asn655Ser	missense	Exon 11 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.1886A>G	p.Asn629Ser	missense	Exon 10 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.1757A>G	p.Asn586Ser	missense	Exon 10 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1627 AN: 152206 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0106 AC: 2661 AN: 251148 AF XY: 0.0105

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00799

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0162 AC: 23653 AN: 1461092 Hom.: 248 Cov.: 30 AF XY: 0.0158 AC XY: 11488 AN XY: 726906

African (AFR) AF: 0.00215 AC: 72 AN: 33462

American (AMR) AF: 0.00523 AC: 234 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 168 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39668

South Asian (SAS) AF: 0.00522 AC: 450 AN: 86244

European-Finnish (FIN) AF: 0.00857 AC: 458 AN: 53414

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5766

European-Non Finnish (NFE) AF: 0.0191 AC: 21274 AN: 1111312

Other (OTH) AF: 0.0156 AC: 940 AN: 60378

GnomAD4 genome AF: 0.0107 AC: 1626 AN: 152324 Hom.: 17 Cov.: 32 AF XY: 0.00918 AC XY: 684 AN XY: 74484

African (AFR) AF: 0.00308 AC: 128 AN: 41578

American (AMR) AF: 0.00706 AC: 108 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1236 AN: 68036

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.0151 Hom.: 91

Bravo AF: 0.0101

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0184 AC: 158

ExAC AF: 0.0105 AC: 1277

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0175

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.87
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.41
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.070
Sift	Benign	0.69	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.047
MPC		0.068
ClinPred		0.0018	T
GERP RS		-1.0
Varity_R		0.029
gMVP		0.25
Mutation Taster		=100/0	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: rs61753893; hg19: chr14-45636328; COSMIC: COSV57497894;