rs147017625

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000135.4(FANCA):c.3524C>T(p.Pro1175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,605,374 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. P1175S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4O:1

Conservation

PhyloP100: 3.27

Publications

4 publications found

Variant links:

Genes affected

FANCA (HGNC:3582): (FA complementation group A) 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 A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA Gene-Disease associations (from GenCC):

Fanconi anemia complementation group A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01314792).

BP6

Variant 16-89745061-G-A is Benign according to our data. Variant chr16-89745061-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134268.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000735 (112/152282) while in subpopulation AFR AF = 0.00257 (107/41554). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.3524C>T	p.Pro1175Leu	missense_variant	Exon 36 of 43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3 link	c.3524C>T	p.Pro1175Leu	missense_variant	Exon 36 of 43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.3524C>T	p.Pro1175Leu	missense_variant	Exon 36 of 43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000301

AC:

AN:

235676

AF XY:

0.000272

show subpopulations

Gnomad AFR exome

AF:

0.00397

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000937

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1453092

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

722874

show subpopulations

African (AFR)

AF:

0.00381

AC:

127

AN:

33374

American (AMR)

AF:

0.0000677

AC:

AN:

44294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26032

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.000315

AC:

AN:

85620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110600

Other (OTH)

AF:

0.000183

AC:

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000735

AC:

112

AN:

152282

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00257

AC:

107

AN:

41554

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000229

Hom.:

Bravo

AF:

0.000880

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Other:1

Jan 19, 2018

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Fanconi anemia

Benign:2

May 10, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hepatoblastoma

Pathogenic:1

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:research

- -

Fanconi anemia complementation group A

Uncertain:1

Apr 14, 2021

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FANCA-related disorder

Benign:1

Jun 12, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Mar 22, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.80

T;T;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

3.3

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.23

B;.;.

Vest4

0.18

MVP

0.92

ClinPred

0.076

GERP RS

3.5

PromoterAI

0.0062

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.17

gMVP

0.33

Mutation Taster

=98/2

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over