16-89749906-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000135.4(FANCA):c.3067-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0771 in 1,613,692 control chromosomes in the GnomAD database, including 5,748 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 417 hom., cov: 33)

Exomes 𝑓: 0.079 ( 5331 hom. )

Consequence

FANCA
NM_000135.4 splice_region, intron

Scores

Splicing: ADA: 0.00004911

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.525

Publications

14 publications found

Variant links:

COSMIC-nc: COSV59795601

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 16-89749906-A-G is Benign according to our data. Variant chr16-89749906-A-G is described in ClinVar as Benign. ClinVar VariationId is 255253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.3067-4T>C		splice_region_variant, intron_variant	Intron 31 of 42	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.3067-4T>C		splice_region_variant, intron_variant	Intron 31 of 42		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.3067-4T>C		splice_region_variant, intron_variant	Intron 31 of 42	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0595

AC:

9060

AN:

152188

Hom.:

416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0372

Gnomad ASJ

AF:

0.0579

Gnomad EAS

AF:

0.216

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0613

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0833

Gnomad OTH

AF:

0.0564

GnomAD2 exomes

AF:

0.0666

AC:

16741

AN:

251340

AF XY:

0.0658

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0584

Gnomad EAS exome

AF:

0.231

Gnomad FIN exome

AF:

0.0594

Gnomad NFE exome

AF:

0.0767

Gnomad OTH exome

AF:

0.0564

GnomAD4 exome

AF:

0.0790

AC:

115387

AN:

1461386

Hom.:

5331

Cov.:

AF XY:

0.0774

AC XY:

56291

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.0113

AC:

379

AN:

33472

American (AMR)

AF:

0.0211

AC:

944

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

1492

AN:

26136

East Asian (EAS)

AF:

0.157

AC:

6248

AN:

39692

South Asian (SAS)

AF:

0.0221

AC:

1903

AN:

86250

European-Finnish (FIN)

AF:

0.0580

AC:

3098

AN:

53374

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.0866

AC:

96260

AN:

1111722

Other (OTH)

AF:

0.0826

AC:

4987

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

5665

11331

16996

22662

28327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3584

7168

10752

14336

17920

<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:

0.0595

AC:

9067

AN:

152306

Hom.:

417

Cov.:

AF XY:

0.0575

AC XY:

4279

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0140

AC:

581

AN:

41576

American (AMR)

AF:

0.0372

AC:

569

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0579

AC:

201

AN:

3470

East Asian (EAS)

AF:

0.217

AC:

1125

AN:

5178

South Asian (SAS)

AF:

0.0271

AC:

131

AN:

4828

European-Finnish (FIN)

AF:

0.0613

AC:

651

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0833

AC:

5667

AN:

68024

Other (OTH)

AF:

0.0568

AC:

120

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

427

853

1280

1706

2133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0592

Hom.:

164

Bravo

AF:

0.0572

Asia WGS

AF:

0.113

AC:

393

AN:

3478

EpiCase

AF:

0.0748

EpiControl

AF:

0.0730

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:5

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.4

(source)

DANN

Benign

0.68

PhyloP100

-0.53

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over