14-45196458-A-G

Variant names:

• chr14-45196458-A-G
• rs45557033
• NM_020937.4:c.5627A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020937.4(FANCM):​c.5627A>G​(p.Asn1876Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,614,114 control chromosomes in the GnomAD database, including 741 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1876T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (59 hom., cov: 32)
  • Exomes 𝑓: 0.028 (682 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.115
• Publications: 12 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=0.0030958652).
• BP6: Variant 14-45196458-A-G is Benign according to our data. Variant chr14-45196458-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3195/152338) while in subpopulation NFE AF = 0.0315 (2146/68028). AF 95% confidence interval is 0.0304. There are 59 homozygotes in GnomAd4. There are 1529 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 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.5627A>G	p.Asn1876Ser	missense	Exon 21 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.5549A>G	p.Asn1850Ser	missense	Exon 20 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.5627A>G	p.Asn1876Ser	missense	Exon 21 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.5549A>G	p.Asn1850Ser	missense	Exon 20 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.5420A>G	p.Asn1807Ser	missense	Exon 20 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3196 AN: 152220 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0210 AC: 5290 AN: 251400 AF XY: 0.0210

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00755

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0473

Gnomad NFE exome AF: 0.0300

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0275 AC: 40227 AN: 1461776 Hom.: 682 Cov.: 33 AF XY: 0.0270 AC XY: 19654 AN XY: 727188

African (AFR) AF: 0.00475 AC: 159 AN: 33478

American (AMR) AF: 0.00776 AC: 347 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 448 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00700 AC: 604 AN: 86254

European-Finnish (FIN) AF: 0.0484 AC: 2586 AN: 53418

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.0312 AC: 34658 AN: 1111924

Other (OTH) AF: 0.0223 AC: 1346 AN: 60392

GnomAD4 genome AF: 0.0210 AC: 3195 AN: 152338 Hom.: 59 Cov.: 32 AF XY: 0.0205 AC XY: 1529 AN XY: 74506

African (AFR) AF: 0.00452 AC: 188 AN: 41576

American (AMR) AF: 0.00961 AC: 147 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4832

European-Finnish (FIN) AF: 0.0498 AC: 529 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2146 AN: 68028

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0270 Hom.: 212

Bravo AF: 0.0174

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0292 AC: 251

ExAC AF: 0.0210 AC: 2556

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 19, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Fanconi anemia Benign:2

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19737859, 29351780)

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Premature ovarian failure 15 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.41
DANN	Benign	0.72
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.12
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.019
Sift	Benign	0.17	T
Sift4G	Uncertain	0.060	T
Polyphen		0.010	B
Vest4		0.057
MPC		0.072
ClinPred		0.0018	T
GERP RS		-4.7
PromoterAI		0.0080	Neutral
Varity_R		0.16
gMVP		0.19
Mutation Taster		=99/1	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: rs45557033; hg19: chr14-45665661; COSMIC: COSV104567027; COSMIC: COSV104567027;