rs45547534

chr14-45137184-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020937.4(FANCM):c.624A>G(p.Ile208Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,613,676 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (11 hom., cov: 32)
  • Exomes 𝑓: 0.015 (183 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0190

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072793067).
• BP6: Variant 14-45137184-A-G is Benign according to our data. Variant chr14-45137184-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 241326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45137184-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1601/152300) while in subpopulation NFE AF= 0.0165 (1121/68024). AF 95% confidence interval is 0.0157. There are 11 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.624A>G	p.Ile208Met	missense_variant	2/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.624A>G	p.Ile208Met	missense_variant	2/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1601 AN: 152182 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0102 AC: 2566 AN: 251204 Hom.: 19 AF XY: 0.0106 AC XY: 1437 AN XY: 135786

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00656

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.0146 AC: 21277 AN: 1461376 Hom.: 183 Cov.: 31 AF XY: 0.0145 AC XY: 10548 AN XY: 727010

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00707

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.00593

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0105 AC: 1601 AN: 152300 Hom.: 11 Cov.: 32 AF XY: 0.00949 AC XY: 707 AN XY: 74474

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0135 Hom.: 29

Bravo AF: 0.0106

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0107 AC: 1296

Asia WGS AF: 0.00433 AC: 17 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2017	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCM p.Ile208Met variant was identified in 6 of 854 proband chromosomes (frequency: 0.007) from individuals with breast or ovarian cancer (Nguyen-Dumont_2018_PMID:29351780). The variant was identified in dbSNP (ID: rs45547534) and ClinVar (classified as benign by ARUP Laboratories and Invitae). The variant was not identified in the Cosmic database and in control databases in 2619 of 268068 chromosomes (22 homozygous) at a frequency of 0.00977 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1778 of 118106 chromosomes (freq: 0.01505), South Asian in 313 of 30522 chromosomes (freq: 0.01025), Other in 63 of 6702 chromosomes (freq: 0.0094), Latino in 237 of 35106 chromosomes (freq: 0.006751), European (Finnish) in 136 of 24908 chromosomes (freq: 0.00546), Ashkenazi Jewish in 37 of 9860 chromosomes (freq: 0.003753) and African in 55 of 23612 chromosomes (freq: 0.002329), but was not observed in the East Asian population. The p.Ile208 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FANCM: BP4, BS1, BS2 -

Premature ovarian failure 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0073	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M;M
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.90	P;D;.
Vest4		0.33
MPC		0.45
ClinPred		0.062	T
GERP RS		0.0078
Varity_R		0.55
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45547534; hg19: chr14-45606387; COSMIC: COSV53531926; COSMIC: COSV53531926;