NM_000135.4:c.1627-32T>C

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.1627-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,592,614 control chromosomes in the GnomAD database, including 504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 40 hom., cov: 32)

Exomes 𝑓: 0.013 ( 464 hom. )

Consequence

FANCA
NM_000135.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.133

Publications

2 publications found

Variant links:

COSMIC-nc: COSV104699326

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=-0.85).

BP6

Variant 16-89779989-A-G is Benign according to our data. Variant chr16-89779989-A-G is described in ClinVar as [Benign]. Clinvar id is 255238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.1627-32T>C		intron_variant	Intron 17 of 42	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.1627-32T>C		intron_variant	Intron 17 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.1627-32T>C		intron_variant	Intron 17 of 42	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2180

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00558

Gnomad SAS

AF:

0.0915

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00930

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0195

AC:

4875

AN:

250046

AF XY:

0.0228

show subpopulations

Gnomad AFR exome

AF:

0.0163

Gnomad AMR exome

AF:

0.00521

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.00354

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.0189

GnomAD4 exome

AF:

0.0128

AC:

18467

AN:

1440294

Hom.:

464

Cov.:

AF XY:

0.0151

AC XY:

10820

AN XY:

717984

show subpopulations

African (AFR)

AF:

0.0177

AC:

584

AN:

33030

American (AMR)

AF:

0.00649

AC:

290

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

465

AN:

26018

East Asian (EAS)

AF:

0.00770

AC:

305

AN:

39600

South Asian (SAS)

AF:

0.0831

AC:

7130

AN:

85810

European-Finnish (FIN)

AF:

0.0125

AC:

668

AN:

53400

Middle Eastern (MID)

AF:

0.0419

AC:

239

AN:

5702

European-Non Finnish (NFE)

AF:

0.00717

AC:

7836

AN:

1092342

Other (OTH)

AF:

0.0159

AC:

950

AN:

59716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1040

2081

3121

4162

5202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0144

AC:

2186

AN:

152320

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1138

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0176

AC:

731

AN:

41578

American (AMR)

AF:

0.00798

AC:

122

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3470

East Asian (EAS)

AF:

0.00559

AC:

AN:

5184

South Asian (SAS)

AF:

0.0915

AC:

442

AN:

4828

European-Finnish (FIN)

AF:

0.0105

AC:

111

AN:

10620

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00931

AC:

633

AN:

68024

Other (OTH)

AF:

0.0161

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

109

218

328

437

546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0134

Hom.:

Bravo

AF:

0.0118

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 29, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.4

(source)

DANN

Benign

0.81

PhyloP100

-0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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NM_000135.4:c.1627-32T>C

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