rs142864437

Variant names:

• chr14-45175613-A-C
• rs142864437
• NM_020937.4:c.2859A>C

Your query was ambiguous. Multiple possible variants found:

• chr14-45175613-A-C
• chr14-45175613-A-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020937.4(FANCM):​c.2859A>C​(p.Lys953Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,613,606 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. K953T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 0.685
• Publications: 11 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011752397).
• BP6: Variant 14-45175613-A-C is Benign according to our data. Variant chr14-45175613-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 313209.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00111 (169/152294) while in subpopulation NFE AF = 0.00206 (140/67992). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.2859A>C	p.Lys953Asn	missense	Exon 14 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.2781A>C	p.Lys927Asn	missense	Exon 13 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.2859A>C	p.Lys953Asn	missense	Exon 14 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.2781A>C	p.Lys927Asn	missense	Exon 13 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.2652A>C	p.Lys884Asn	missense	Exon 13 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00110 AC: 275 AN: 249790 AF XY: 0.00105

Gnomad AFR exome AF: 0.000443

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.00194 AC: 2839 AN: 1461312 Hom.: 4 Cov.: 32 AF XY: 0.00185 AC XY: 1343 AN XY: 726974

African (AFR) AF: 0.000389 AC: 13 AN: 33460

American (AMR) AF: 0.000962 AC: 43 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86244

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53254

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00238 AC: 2642 AN: 1111728

Other (OTH) AF: 0.00167 AC: 101 AN: 60376

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74474

African (AFR) AF: 0.000241 AC: 10 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 67992

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00172 Hom.: 3

Bravo AF: 0.00112

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00111 AC: 135

EpiCase AF: 0.00175

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	FANCM-related disorder (1)
-	-	1	Fanconi anemia (1)
-	1	-	Hepatoblastoma (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (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	0.19
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.69
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.085
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.060	T
Polyphen		0.99	D
Vest4		0.41
MutPred		0.32		Loss of ubiquitination at K953 (P = 0.0027)
MVP		0.53
MPC		0.50
ClinPred		0.039	T
GERP RS		1.2
PromoterAI		0.0050	Neutral
Varity_R		0.15
gMVP		0.26
Mutation Taster		=97/3	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: rs142864437; hg19: chr14-45644816; COSMIC: COSV99032233; COSMIC: COSV99032233;