rs61730251

Variant names:

• chr14-45176674-A-G
• rs61730251
• NM_020937.4:c.3920A>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.3920A>G​(p.Tyr1307Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,613,804 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1307H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.03
• Publications: 3 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=0.0035254955).
• BP6: Variant 14-45176674-A-G is Benign according to our data. Variant chr14-45176674-A-G is described in ClinVar as Benign. ClinVar VariationId is 241320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00429 (653/152306) while in subpopulation AFR AF = 0.0147 (612/41560). AF 95% confidence interval is 0.0138. There are 5 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.3920A>G	p.Tyr1307Cys	missense	Exon 14 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.3842A>G	p.Tyr1281Cys	missense	Exon 13 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.3920A>G	p.Tyr1307Cys	missense	Exon 14 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.3842A>G	p.Tyr1281Cys	missense	Exon 13 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.3713A>G	p.Tyr1238Cys	missense	Exon 13 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 654 AN: 152188 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00123 AC: 308 AN: 250856 AF XY: 0.000804

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000478 AC: 698 AN: 1461498 Hom.: 7 Cov.: 32 AF XY: 0.000399 AC XY: 290 AN XY: 727060

African (AFR) AF: 0.0168 AC: 562 AN: 33464

American (AMR) AF: 0.000939 AC: 42 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111822

Other (OTH) AF: 0.00123 AC: 74 AN: 60378

GnomAD4 genome AF: 0.00429 AC: 653 AN: 152306 Hom.: 5 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74466

African (AFR) AF: 0.0147 AC: 612 AN: 41560

American (AMR) AF: 0.00183 AC: 28 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00181 Hom.: 1

Bravo AF: 0.00543

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00159 AC: 193

Asia WGS AF: 0.00145 AC: 5 AN: 3472

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (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	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.14
DANN	Benign	0.17
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.0
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.031
Sift	Benign	0.29	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.045
MVP		0.13
MPC		0.11
ClinPred		0.0034	T
GERP RS		-4.4
Varity_R		0.036
gMVP		0.33
Mutation Taster		=99/1	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: rs61730251; hg19: chr14-45645877; COSMIC: COSV99951694; COSMIC: COSV99951694;