rs144215747

Variant names:

• chr14-45159275-C-G
• rs144215747
• NM_020937.4:c.1576C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_020937.4(FANCM):​c.1576C>G​(p.Leu526Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,609,804 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L526Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 0.954
• Publications: 9 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020171225).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00141 (214/152170) while in subpopulation AMR AF = 0.0055 (84/15270). AF 95% confidence interval is 0.00455. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.1576C>G	p.Leu526Val	missense	Exon 9 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.1498C>G	p.Leu500Val	missense	Exon 8 of 22	NP_001295062.1
	FANCM	NM_001308134.2		c.1576C>G	p.Leu526Val	missense	Exon 9 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.1576C>G	p.Leu526Val	missense	Exon 9 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.1498C>G	p.Leu500Val	missense	Exon 8 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.1576C>G	p.Leu526Val	missense	Exon 9 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152052 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000980 AC: 245 AN: 250030 AF XY: 0.000902

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00176 AC: 2559 AN: 1457634 Hom.: 6 Cov.: 29 AF XY: 0.00167 AC XY: 1211 AN XY: 725360

African (AFR) AF: 0.000299 AC: 10 AN: 33396

American (AMR) AF: 0.00182 AC: 81 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85850

European-Finnish (FIN) AF: 0.000469 AC: 25 AN: 53352

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00215 AC: 2383 AN: 1108708

Other (OTH) AF: 0.000963 AC: 58 AN: 60236

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152170 Hom.: 1 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74384

African (AFR) AF: 0.000385 AC: 16 AN: 41530

American (AMR) AF: 0.00550 AC: 84 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.000945 AC: 10 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00150 Hom.: 3

Bravo AF: 0.00156

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000890 AC: 108

EpiCase AF: 0.00159

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	-	1	FANCM-related disorder (1)
-	-	1	Fanconi anemia (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Spermatogenic failure 28 (1)
-	1	-	Spermatogenic failure 28;C4748170:Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.95
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.052
Sift	Benign	0.033	D
Sift4G	Uncertain	0.039	D
Polyphen		0.0020	B
Vest4		0.27
MVP		0.59
MPC		0.090
ClinPred		0.031	T
GERP RS		3.4
Varity_R		0.14
gMVP		0.55
Mutation Taster		=54/46	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: rs144215747; hg19: chr14-45628478; COSMIC: COSV57504138;