rs8017226

Variant names:

• chr14-45175424-T-C
• rs8017226
• NM_020937.4:c.2670T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020937.4(FANCM):​c.2670T>C​(p.Phe890Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,584,180 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (225 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (210 hom.)
• Consequence: FANCM NM_020937.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.327
• 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):

• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-45175424-T-C is Benign according to our data. Variant chr14-45175424-T-C is described in ClinVar as Benign. ClinVar VariationId is 313207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.327 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.2670T>C	p.Phe890Phe	synonymous	Exon 14 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.2592T>C	p.Phe864Phe	synonymous	Exon 13 of 22	NP_001295062.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.2670T>C	p.Phe890Phe	synonymous	Exon 14 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.2592T>C	p.Phe864Phe	synonymous	Exon 13 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.2463T>C	p.Phe821Phe	synonymous	Exon 13 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4381 AN: 152146 Hom.: 228 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00790 AC: 1825 AN: 231040 AF XY: 0.00593

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00293 AC: 4200 AN: 1431918 Hom.: 210 Cov.: 30 AF XY: 0.00256 AC XY: 1823 AN XY: 711120

African (AFR) AF: 0.105 AC: 3336 AN: 31810

American (AMR) AF: 0.00648 AC: 253 AN: 39026

Ashkenazi Jewish (ASJ) AF: 0.00192 AC: 48 AN: 24974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.0000619 AC: 5 AN: 80720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52782

Middle Eastern (MID) AF: 0.00411 AC: 23 AN: 5594

European-Non Finnish (NFE) AF: 0.000133 AC: 146 AN: 1098442

Other (OTH) AF: 0.00658 AC: 389 AN: 59128

GnomAD4 genome AF: 0.0288 AC: 4387 AN: 152262 Hom.: 225 Cov.: 32 AF XY: 0.0279 AC XY: 2078 AN XY: 74474

African (AFR) AF: 0.101 AC: 4183 AN: 41534

American (AMR) AF: 0.00857 AC: 131 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 68004

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.00888 Hom.: 68

Bravo AF: 0.0322

Asia WGS AF: 0.00463 AC: 16 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.63
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs8017226; hg19: chr14-45644627; COSMIC: COSV104566901;