rs139382267

Variant names:

• chr14-45176050-G-A
• rs139382267
• NM_020937.4:c.3296G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-45176050-G-A
• chr14-45176050-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020937.4(FANCM):​c.3296G>A​(p.Arg1099His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R1099S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 1.87
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043137074).
• BP6: Variant 14-45176050-G-A is Benign according to our data. Variant chr14-45176050-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414849.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000814 (124/152244) while in subpopulation AFR AF = 0.00217 (90/41548). AF 95% confidence interval is 0.0018. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3296G>A	p.Arg1099His	missense	Exon 14 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.3218G>A	p.Arg1073His	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.3296G>A	p.Arg1099His	missense	Exon 14 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.3218G>A	p.Arg1073His	missense	Exon 13 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.3089G>A	p.Arg1030His	missense	Exon 13 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000355 AC: 89 AN: 250628 AF XY: 0.000332

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461736 Hom.: 0 Cov.: 33 AF XY: 0.000237 AC XY: 172 AN XY: 727164

African (AFR) AF: 0.00227 AC: 76 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111908

Other (OTH) AF: 0.000464 AC: 28 AN: 60388

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74418

African (AFR) AF: 0.00217 AC: 90 AN: 41548

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000802 Hom.: 0

Bravo AF: 0.000846

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Aplastic anemia (1)
-	-	1	FANCM-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group A (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)
-	-	1	Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.3
DANN	Benign	0.11
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00067	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.0	N
PhyloP100		1.9
PrimateAI	Benign	0.18	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	0.79	T
Polyphen		0.0010	B
Vest4		0.024
MVP		0.19
MPC		0.11
ClinPred		0.0031	T
GERP RS		3.0
PromoterAI		0.012	Neutral
Varity_R		0.020
gMVP		0.30
Mutation Taster		=98/2	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: rs139382267; hg19: chr14-45645253;