rs147021911

Variant names:

• chr14-45189123-C-T
• rs147021911
• NM_020937.4:c.5101C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 20P and 5B. PVS1 PS3 PP5_Very_Strong BS1_Supporting BS2

The NM_020937.4(FANCM):​c.5101C>T​(p.Gln1701*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,613,978 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000554073: Experimental studies have shown that this premature translational stop signal affects FANCM function (PMID:31700994). This variant disrupts the C-terminal ERCC4 nuclease domain and the helix-hairpin-helix (HhH) motifs of the FANCM protein, which are critical for the interaction between FANCM and FAAP24, chromatin localization of the FANCM/FAAP24 complex and the activation of the FA core complex (PMID:17289582, 23932590, 18174376, 19379763, 24003026)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1701Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (2 hom.)
• Consequence: FANCM NM_020937.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 U:1
• Conservation: PhyloP100: 0.927
• Publications: 68 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):

• FANCM Fanconi-like genomic instability disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, ClinGen
• 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
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000554073: Experimental studies have shown that this premature translational stop signal affects FANCM function (PMID: 31700994). This variant disrupts the C-terminal ERCC4 nuclease domain and the helix-hairpin-helix (HhH) motifs of the FANCM protein, which are critical for the interaction between FANCM and FAAP24, chromatin localization of the FANCM/FAAP24 complex and the activation of the FA core complex (PMID: 17289582, 23932590, 18174376, 19379763, 24003026).; SCV001817166: Published functional studies suggest a damaging effect: increased chromosome fragility, decreased cell survival, and reduced monoubiquination of FANCM in response to MMC and DEB exposure (PMID: 29231814, 31700994); SCV004218815: Functional studies found that this variant increased chromosome fragility, decreased DNA repair activity, and absent protein expression (PMIDs: 29231814 (2017) and 31700994 (2019)).; SCV001424775: "functional studies suggest this variant may not lead to nonsense mediated decay (Kiiski 2014)."
• PP5: Variant 14-45189123-C-T is Pathogenic according to our data. Variant chr14-45189123-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 412519.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 = 0.000985 (150/152328) while in subpopulation NFE AF = 0.000838 (57/68028). AF 95% confidence interval is 0.000664. There are 1 homozygotes in GnomAd4. There are 99 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 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.5101C>T	p.Gln1701*	stop_gained	Exon 20 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.5023C>T	p.Gln1675*	stop_gained	Exon 19 of 22	NP_001295062.1	Q8IYD8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.5101C>T	p.Gln1701*	stop_gained	Exon 20 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.5023C>T	p.Gln1675*	stop_gained	Exon 19 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.4894C>T	p.Gln1632*	stop_gained	Exon 19 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00125 AC: 313 AN: 251238 AF XY: 0.00127

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00822

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000952 AC: 1391 AN: 1461650 Hom.: 2 Cov.: 32 AF XY: 0.000932 AC XY: 678 AN XY: 727146

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00957 AC: 511 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000738 AC: 821 AN: 1111806

Other (OTH) AF: 0.000878 AC: 53 AN: 60376

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74478

African (AFR) AF: 0.0000721 AC: 3 AN: 41588

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00820 AC: 87 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68028

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000863 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	1	-	not provided (5)
2	-	-	Fanconi anemia (2)
2	-	-	Premature ovarian failure 15 (2)
2	-	-	Spermatogenic failure 28;C4748170:Premature ovarian failure 15 (2)
1	-	-	Familial cancer of breast (1)
1	-	-	FANCM-related disorder (1)
1	-	-	Fanconi anemia complementation group A (1)
1	-	-	Male infertility with spermatogenesis disorder (1)
1	-	-	Spermatogenic failure 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.31	N
PhyloP100		0.93
Vest4		0.79
ClinPred		0.16	T
GERP RS		-2.5
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs147021911; hg19: chr14-45658326; COSMIC: COSV57498280; COSMIC: COSV57498280;