NM_020937.4:c.2268C>A

Variant names:

• chr14-45173162-C-A
• rs146061601
• NM_020937.4:c.2268C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020937.4(FANCM):​c.2268C>A​(p.Arg756Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,700 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: FANCM NM_020937.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.228
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 14-45173162-C-A is Benign according to our data. Variant chr14-45173162-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.228 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00127 (193/152220) while in subpopulation NFE AF = 0.00249 (169/68004). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.2268C>A	p.Arg756Arg	synonymous	Exon 13 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.2190C>A	p.Arg730Arg	synonymous	Exon 12 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.2268C>A	p.Arg756Arg	synonymous	Exon 13 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.2190C>A	p.Arg730Arg	synonymous	Exon 12 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.2061C>A	p.Arg687Arg	synonymous	Exon 12 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00112 AC: 281 AN: 251228 AF XY: 0.000994

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00220 AC: 3210 AN: 1461480 Hom.: 7 Cov.: 30 AF XY: 0.00212 AC XY: 1539 AN XY: 727072

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.000179 AC: 8 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00277 AC: 3077 AN: 1111708

Other (OTH) AF: 0.00141 AC: 85 AN: 60376

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74408

African (AFR) AF: 0.000409 AC: 17 AN: 41536

American (AMR) AF: 0.000196 AC: 3 AN: 15296

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00249 AC: 169 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	7.0
DANN	Benign	0.58
PhyloP100		-0.23
Mutation Taster		=99/1	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: rs146061601; hg19: chr14-45642365; COSMIC: COSV104566947;