16-89777635-T-C

Variant names:

• chr16-89777635-T-C
• rs1006548
• NM_000135.4:c.1826+1166A>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+1166A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 151,774 control chromosomes in the GnomAD database, including 15,382 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 0.41 (15382 hom., cov: 30)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 13 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 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+1166A>G		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.1826+1166A>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+1166A>G		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.1826+1166A>G		intron	N/A	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.1826+1166A>G		intron	N/A	ENSP00000454977.2

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61757 AN: 151656 Hom.: 15358 Cov.: 30

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.407 AC: 61841 AN: 151774 Hom.: 15382 Cov.: 30 AF XY: 0.422 AC XY: 31310 AN XY: 74164

African (AFR) AF: 0.631 AC: 26099 AN: 41378

American (AMR) AF: 0.484 AC: 7376 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 677 AN: 3468

East Asian (EAS) AF: 0.754 AC: 3870 AN: 5132

South Asian (SAS) AF: 0.597 AC: 2871 AN: 4808

European-Finnish (FIN) AF: 0.352 AC: 3706 AN: 10526

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16165 AN: 67926

Other (OTH) AF: 0.377 AC: 794 AN: 2104

Alfa AF: 0.289 Hom.: 2720

Bravo AF: 0.426

Asia WGS AF: 0.665 AC: 2313 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-0.13
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: rs1006548; hg19: chr16-89844043;