rs61746943

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020937.4(FANCM):c.4799C>T(p.Thr1600Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,611,134 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. T1600A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 25 hom., cov: 32)

Exomes 𝑓: 0.020 ( 374 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.30

Publications

13 publications found

Variant links:

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

FANCM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061993003).

BP6

Variant 14-45188821-C-T is Benign according to our data. Variant chr14-45188821-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218780.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 = 0.0154 (2346/152068) while in subpopulation NFE AF = 0.0224 (1522/68008). AF 95% confidence interval is 0.0214. There are 25 homozygotes in GnomAd4. There are 1170 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 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.4799C>T	p.Thr1600Ile	missense	Exon 20 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.4721C>T	p.Thr1574Ile	missense	Exon 19 of 22	NP_001295062.1	Q8IYD8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCM	ENST00000267430.10	TSL:1 MANE Select	c.4799C>T	p.Thr1600Ile	missense	Exon 20 of 23	ENSP00000267430.5	Q8IYD8-1
FANCM	ENST00000542564.6	TSL:1	c.4721C>T	p.Thr1574Ile	missense	Exon 19 of 22	ENSP00000442493.2	Q8IYD8-3
FANCM	ENST00000556250.6	TSL:1	c.4592C>T	p.Thr1531Ile	missense	Exon 19 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2347

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00307

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0439

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.0176

AC:

4391

AN:

250098

AF XY:

0.0172

show subpopulations

Gnomad AFR exome

AF:

0.00285

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.0241

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0429

Gnomad NFE exome

AF:

0.0245

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.0196

AC:

28572

AN:

1459066

Hom.:

374

Cov.:

AF XY:

0.0193

AC XY:

14031

AN XY:

726008

show subpopulations

African (AFR)

AF:

0.00305

AC:

102

AN:

33414

American (AMR)

AF:

0.00734

AC:

328

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.0240

AC:

627

AN:

26104

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39634

South Asian (SAS)

AF:

0.00175

AC:

151

AN:

86112

European-Finnish (FIN)

AF:

0.0427

AC:

2278

AN:

53386

Middle Eastern (MID)

AF:

0.000388

AC:

AN:

5150

European-Non Finnish (NFE)

AF:

0.0217

AC:

24136

AN:

1110336

Other (OTH)

AF:

0.0157

AC:

947

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

1258

2515

3773

5030

6288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

870

1740

2610

3480

4350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2346

AN:

152068

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1170

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00306

AC:

127

AN:

41454

American (AMR)

AF:

0.00726

AC:

111

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0439

AC:

462

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0224

AC:

1522

AN:

68008

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0209

Hom.:

125

Bravo

AF:

0.0125

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0244

AC:

210

ExAC

AF:

0.0182

AC:

2204

Asia WGS

AF:

0.00173

AC:

AN:

3474

EpiCase

AF:

0.0186

EpiControl

AF:

0.0182

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Fanconi anemia (2)

not provided (2)

Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.0098

Eigen_PC

Benign

-0.048

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.4

PhyloP100

1.3

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.26

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.014

Polyphen

0.93

Vest4

0.11

MPC

0.31

ClinPred

0.018

GERP RS

2.7

Varity_R

0.13

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over