NM_000135.4:c.3066+457T>C

Variant names:

• chr16-89751681-A-G
• rs9926296
• NM_000135.4:c.3066+457T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000135.4(FANCA):​c.3066+457T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,870 control chromosomes in the GnomAD database, including 23,223 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23223 hom., cov: 30)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.986
• Publications: 35 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.3066+457T>C		intron_variant	Intron 31 of 42	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.3066+457T>C		intron_variant	Intron 31 of 42		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.3066+457T>C		intron_variant	Intron 31 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82062 AN: 151752 Hom.: 23189 Cov.: 30

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.472

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.541 AC: 82150 AN: 151870 Hom.: 23223 Cov.: 30 AF XY: 0.549 AC XY: 40764 AN XY: 74214

African (AFR) AF: 0.601 AC: 24863 AN: 41392

American (AMR) AF: 0.552 AC: 8422 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1403 AN: 3468

East Asian (EAS) AF: 0.982 AC: 5055 AN: 5150

South Asian (SAS) AF: 0.630 AC: 3035 AN: 4816

European-Finnish (FIN) AF: 0.536 AC: 5649 AN: 10530

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32263 AN: 67948

Other (OTH) AF: 0.477 AC: 1005 AN: 2106

Alfa AF: 0.502 Hom.: 55558

Bravo AF: 0.547

Asia WGS AF: 0.787 AC: 2736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.49
DANN	Benign	0.25
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs9926296; hg19: chr16-89818089;