14-45175386-G-T

Variant names:

• chr14-45175386-G-T
• rs1367580
• NM_020937.4:c.2632G>T

Variant summary

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

The ENST00000267430.10(FANCM):​c.2632G>T​(p.Val878Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,557,268 control chromosomes in the GnomAD database, including 16,851 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3656 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13195 hom.)
• Consequence: FANCM ENST00000267430.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.306
• Publications: 39 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=0.0020548701).
• BP6: Variant 14-45175386-G-T is Benign according to our data. Variant chr14-45175386-G-T is described in ClinVar as Benign. ClinVar VariationId is 261383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000267430.10. 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.2632G>T	p.Val878Leu	missense	Exon 14 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.2554G>T	p.Val852Leu	missense	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.2632G>T	p.Val878Leu	missense	Exon 14 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.2554G>T	p.Val852Leu	missense	Exon 13 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.2425G>T	p.Val809Leu	missense	Exon 13 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29070 AN: 151992 Hom.: 3625 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.149 AC: 33860 AN: 227958 AF XY: 0.145

Gnomad AFR exome AF: 0.355

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.128 AC: 179749 AN: 1405158 Hom.: 13195 Cov.: 28 AF XY: 0.129 AC XY: 90285 AN XY: 699202

African (AFR) AF: 0.358 AC: 11023 AN: 30772

American (AMR) AF: 0.166 AC: 6243 AN: 37644

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3497 AN: 24618

East Asian (EAS) AF: 0.140 AC: 5512 AN: 39308

South Asian (SAS) AF: 0.185 AC: 14665 AN: 79266

European-Finnish (FIN) AF: 0.121 AC: 6385 AN: 52606

Middle Eastern (MID) AF: 0.161 AC: 888 AN: 5516

European-Non Finnish (NFE) AF: 0.114 AC: 123211 AN: 1077362

Other (OTH) AF: 0.143 AC: 8325 AN: 58066

GnomAD4 genome AF: 0.192 AC: 29154 AN: 152110 Hom.: 3656 Cov.: 32 AF XY: 0.190 AC XY: 14147 AN XY: 74370

African (AFR) AF: 0.355 AC: 14719 AN: 41478

American (AMR) AF: 0.167 AC: 2554 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3470

East Asian (EAS) AF: 0.135 AC: 701 AN: 5178

South Asian (SAS) AF: 0.188 AC: 905 AN: 4826

European-Finnish (FIN) AF: 0.108 AC: 1144 AN: 10594

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8042 AN: 67962

Other (OTH) AF: 0.189 AC: 399 AN: 2110

Alfa AF: 0.139 Hom.: 7211

Bravo AF: 0.201

TwinsUK AF: 0.111 AC: 412

ALSPAC AF: 0.112 AC: 433

ESP6500AA AF: 0.333 AC: 1460

ESP6500EA AF: 0.119 AC: 1020

ExAC AF: 0.156 AC: 18878

Asia WGS AF: 0.169 AC: 590 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Premature ovarian failure 15 (3)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Spermatogenic failure 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.81
DANN	Benign	0.098
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.0	N
PhyloP100		0.31
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.098
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.013
MutPred		0.21		Gain of catalytic residue at D876 (P = 0.0031)
MPC		0.083
ClinPred		0.0037	T
GERP RS		4.1
Varity_R		0.043
gMVP		0.092
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: rs1367580; hg19: chr14-45644589; COSMIC: COSV57497457; COSMIC: COSV57497457;