14-45137084-C-T

Variant names:

• chr14-45137084-C-T
• rs10138997
• NM_020937.4:c.524C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020937.4(FANCM):​c.524C>T​(p.Ser175Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 1,611,518 control chromosomes in the GnomAD database, including 10,272 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S175P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (3753 hom., cov: 33)
  • Exomes 𝑓: 0.072 (6519 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0520
• Publications: 35 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025475323).
• BP6: Variant 14-45137084-C-T is Benign according to our data. Variant chr14-45137084-C-T is described in ClinVar as Benign. ClinVar VariationId is 261389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.397 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.524C>T	p.Ser175Phe	missense	Exon 2 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.524C>T	p.Ser175Phe	missense	Exon 2 of 22	NP_001295062.1
	FANCM	NM_001308134.2		c.524C>T	p.Ser175Phe	missense	Exon 2 of 11	NP_001295063.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.524C>T	p.Ser175Phe	missense	Exon 2 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.524C>T	p.Ser175Phe	missense	Exon 2 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.524C>T	p.Ser175Phe	missense	Exon 2 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24713 AN: 152020 Hom.: 3720 Cov.: 33

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0915

Gnomad ASJ AF: 0.0643

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0818

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.101 AC: 25456 AN: 251258 AF XY: 0.0964

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.0835

Gnomad ASJ exome AF: 0.0694

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.0878

Gnomad NFE exome AF: 0.0581

Gnomad OTH exome AF: 0.0806

GnomAD4 exome AF: 0.0721 AC: 105260 AN: 1459380 Hom.: 6519 Cov.: 30 AF XY: 0.0727 AC XY: 52796 AN XY: 726182

African (AFR) AF: 0.411 AC: 13683 AN: 33324

American (AMR) AF: 0.0853 AC: 3816 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 1829 AN: 26116

East Asian (EAS) AF: 0.136 AC: 5394 AN: 39656

South Asian (SAS) AF: 0.127 AC: 10979 AN: 86196

European-Finnish (FIN) AF: 0.0912 AC: 4855 AN: 53222

Middle Eastern (MID) AF: 0.0926 AC: 531 AN: 5732

European-Non Finnish (NFE) AF: 0.0529 AC: 58751 AN: 1110124

Other (OTH) AF: 0.0899 AC: 5422 AN: 60290

GnomAD4 genome AF: 0.163 AC: 24798 AN: 152138 Hom.: 3753 Cov.: 33 AF XY: 0.161 AC XY: 12006 AN XY: 74408

African (AFR) AF: 0.403 AC: 16688 AN: 41450

American (AMR) AF: 0.0911 AC: 1394 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 223 AN: 3470

East Asian (EAS) AF: 0.127 AC: 658 AN: 5182

South Asian (SAS) AF: 0.129 AC: 624 AN: 4822

European-Finnish (FIN) AF: 0.0818 AC: 867 AN: 10604

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0575 AC: 3908 AN: 67996

Other (OTH) AF: 0.147 AC: 311 AN: 2114

Alfa AF: 0.0936 Hom.: 4842

Bravo AF: 0.173

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0509 AC: 196

ESP6500AA AF: 0.395 AC: 1741

ESP6500EA AF: 0.0552 AC: 475

ExAC AF: 0.109 AC: 13269

Asia WGS AF: 0.136 AC: 476 AN: 3478

EpiCase AF: 0.0543

EpiControl AF: 0.0606

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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.013	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.052
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.060
Sift	Benign	0.055	T
Sift4G	Uncertain	0.055	T
Polyphen		0.0010	B
Vest4		0.052
MPC		0.094
ClinPred		0.0041	T
GERP RS		4.2
Varity_R		0.076
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs10138997; hg19: chr14-45606287; COSMIC: COSV53531409; COSMIC: COSV53531409;