16-89748410-T-G

Variant names:

• chr16-89748410-T-G
• rs2011877
• NM_000135.4:c.3348+249A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.3348+249A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 152,148 control chromosomes in the GnomAD database, including 15,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.43 (15340 hom., cov: 33)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.01
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-89748410-T-G is Benign according to our data. Variant chr16-89748410-T-G is described in ClinVar as Benign. ClinVar VariationId is 1279666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 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.3348+249A>C		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.3348+249A>C		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.3348+249A>C		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000564475.6	TSL:2	c.3348+249A>C		intron	N/A	ENSP00000454977.2
	FANCA	ENST00000568369.6	TSL:2	c.3348+249A>C		intron	N/A	ENSP00000456829.1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64609 AN: 152030 Hom.: 15312 Cov.: 33

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.374

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

GnomAD4 genome AF: 0.425 AC: 64697 AN: 152148 Hom.: 15340 Cov.: 33 AF XY: 0.437 AC XY: 32495 AN XY: 74384

African (AFR) AF: 0.577 AC: 23956 AN: 41504

American (AMR) AF: 0.494 AC: 7546 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 864 AN: 3470

East Asian (EAS) AF: 0.758 AC: 3919 AN: 5168

South Asian (SAS) AF: 0.500 AC: 2417 AN: 4830

European-Finnish (FIN) AF: 0.405 AC: 4288 AN: 10594

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20591 AN: 67992

Other (OTH) AF: 0.379 AC: 800 AN: 2110

Alfa AF: 0.310 Hom.: 3988

Bravo AF: 0.445

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.023
DANN	Benign	0.71
PhyloP100		-3.0
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: rs2011877; hg19: chr16-89814818;