14-45196265-C-G

Variant names:

• chr14-45196265-C-G
• rs3736772
• NM_020937.4:c.5434C>G

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.5434C>G​(p.Pro1812Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,652 control chromosomes in the GnomAD database, including 10,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. P1812L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.087 (757 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9725 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.37
• Publications: 28 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=0.0012592673).
• BP6: Variant 14-45196265-C-G is Benign according to our data. Variant chr14-45196265-C-G is described in ClinVar as Benign. ClinVar VariationId is 261390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.5434C>G	p.Pro1812Ala	missense	Exon 21 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.5356C>G	p.Pro1786Ala	missense	Exon 20 of 22	NP_001295062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.5434C>G	p.Pro1812Ala	missense	Exon 21 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.5356C>G	p.Pro1786Ala	missense	Exon 20 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.5227C>G	p.Pro1743Ala	missense	Exon 20 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.0868 AC: 13205 AN: 152064 Hom.: 758 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.116 AC: 29247 AN: 251378 AF XY: 0.121

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.109 AC: 159686 AN: 1461470 Hom.: 9725 Cov.: 33 AF XY: 0.112 AC XY: 81710 AN XY: 727048

African (AFR) AF: 0.0175 AC: 585 AN: 33466

American (AMR) AF: 0.113 AC: 5055 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3686 AN: 26126

East Asian (EAS) AF: 0.123 AC: 4870 AN: 39682

South Asian (SAS) AF: 0.200 AC: 17272 AN: 86250

European-Finnish (FIN) AF: 0.123 AC: 6573 AN: 53420

Middle Eastern (MID) AF: 0.136 AC: 783 AN: 5768

European-Non Finnish (NFE) AF: 0.103 AC: 114127 AN: 1111672

Other (OTH) AF: 0.112 AC: 6735 AN: 60372

GnomAD4 genome AF: 0.0868 AC: 13206 AN: 152182 Hom.: 757 Cov.: 32 AF XY: 0.0889 AC XY: 6615 AN XY: 74388

African (AFR) AF: 0.0221 AC: 918 AN: 41534

American (AMR) AF: 0.100 AC: 1534 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3472

East Asian (EAS) AF: 0.119 AC: 617 AN: 5178

South Asian (SAS) AF: 0.196 AC: 946 AN: 4820

European-Finnish (FIN) AF: 0.111 AC: 1171 AN: 10568

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7128 AN: 68004

Other (OTH) AF: 0.111 AC: 234 AN: 2114

Alfa AF: 0.0973 Hom.: 665

Bravo AF: 0.0823

TwinsUK AF: 0.0947 AC: 351

ALSPAC AF: 0.0955 AC: 368

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.106 AC: 910

ExAC AF: 0.116 AC: 14054

Asia WGS AF: 0.133 AC: 461 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.108

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)
-	-	2	Premature ovarian failure 15 (2)
-	-	1	Spermatogenic failure 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.034
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.10
MPC		0.087
ClinPred		0.013	T
GERP RS		3.3
PromoterAI		-0.022	Neutral
Varity_R		0.081
gMVP		0.24
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: rs3736772; hg19: chr14-45665468; COSMIC: COSV57498076; COSMIC: COSV57498076;