16-89784625-C-T

Variant names:

• chr16-89784625-C-T
• rs16966142
• NM_000135.4:c.1470+229G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000135.4(FANCA):​c.1470+229G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 151,924 control chromosomes in the GnomAD database, including 2,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (2615 hom., cov: 31)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.496
• Publications: 23 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-89784625-C-T is Benign according to our data. Variant chr16-89784625-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233958.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.1470+229G>A		intron_variant	Intron 15 of 42	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.1470+229G>A		intron_variant	Intron 15 of 42		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.1470+229G>A		intron_variant	Intron 15 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22127 AN: 151806 Hom.: 2611 Cov.: 31

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0847

Gnomad OTH AF: 0.127

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

GnomAD4 genome AF: 0.146 AC: 22142 AN: 151924 Hom.: 2615 Cov.: 31 AF XY: 0.159 AC XY: 11805 AN XY: 74226

African (AFR) AF: 0.127 AC: 5268 AN: 41444

American (AMR) AF: 0.272 AC: 4141 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3470

East Asian (EAS) AF: 0.594 AC: 3062 AN: 5156

South Asian (SAS) AF: 0.183 AC: 884 AN: 4820

European-Finnish (FIN) AF: 0.237 AC: 2491 AN: 10522

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0847 AC: 5753 AN: 67956

Other (OTH) AF: 0.129 AC: 273 AN: 2110

Alfa AF: 0.110 Hom.: 4847

Bravo AF: 0.153

Asia WGS AF: 0.344 AC: 1197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 24, 2019

GeneDx

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	-0.90
CADD	Benign	2.1
DANN	Benign	0.52
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16966142; hg19: chr16-89851033;