16-89777821-T-C

Variant names:

• chr16-89777821-T-C
• rs1006547
• NM_000135.4:c.1826+980A>G

Variant summary

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

The NM_000135.4(FANCA):​c.1826+980A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,770 control chromosomes in the GnomAD database, including 13,588 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 0.40 (13588 hom., cov: 30)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183
• Publications: 15 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000135.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.1826+980A>G		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.1826+980A>G		intron	N/A	NP_001273096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.1826+980A>G		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.1826+980A>G		intron	N/A	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.1826+980A>G		intron	N/A	ENSP00000454977.2

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61306 AN: 151648 Hom.: 13576 Cov.: 30

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.404 AC: 61369 AN: 151770 Hom.: 13588 Cov.: 30 AF XY: 0.417 AC XY: 30923 AN XY: 74162

African (AFR) AF: 0.511 AC: 21144 AN: 41402

American (AMR) AF: 0.480 AC: 7317 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3466

East Asian (EAS) AF: 0.749 AC: 3842 AN: 5132

South Asian (SAS) AF: 0.509 AC: 2449 AN: 4808

European-Finnish (FIN) AF: 0.400 AC: 4209 AN: 10512

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20467 AN: 67912

Other (OTH) AF: 0.363 AC: 762 AN: 2102

Alfa AF: 0.338 Hom.: 25902

Bravo AF: 0.418

Asia WGS AF: 0.614 AC: 2135 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.74
PhyloP100		-0.18
Mutation Taster		=99/1	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: rs1006547; hg19: chr16-89844229;