16-89778786-A-G

Position:

• chr16-89778786-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.1826+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,608,578 control chromosomes in the GnomAD database, including 180,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22371 hom., cov: 32)
  • Exomes 𝑓: 0.45 (157808 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.36

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-89778786-A-G is Benign according to our data. Variant chr16-89778786-A-G is described in ClinVar as [Benign]. Clinvar id is 255241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89778786-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.1826+15T>C		intron_variant		ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.1826+15T>C		intron_variant			NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.1826+15T>C		intron_variant		1	NM_000135.4	ENSP00000373952	P1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78573 AN: 151764 Hom.: 22344 Cov.: 32

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.453

GnomAD3 exomes AF: 0.516 AC: 129841 AN: 251404 Hom.: 37947 AF XY: 0.505 AC XY: 68667 AN XY: 135882

Gnomad AFR exome AF: 0.691

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.984

Gnomad SAS exome AF: 0.592

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.450

GnomAD4 exome AF: 0.449 AC: 653579 AN: 1456700 Hom.: 157808 Cov.: 34 AF XY: 0.450 AC XY: 326300 AN XY: 724980

Gnomad4 AFR exome AF: 0.691

Gnomad4 AMR exome AF: 0.647

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.980

Gnomad4 SAS exome AF: 0.591

Gnomad4 FIN exome AF: 0.464

Gnomad4 NFE exome AF: 0.405

Gnomad4 OTH exome AF: 0.463

GnomAD4 genome AF: 0.518 AC: 78660 AN: 151878 Hom.: 22371 Cov.: 32 AF XY: 0.528 AC XY: 39189 AN XY: 74200

Gnomad4 AFR AF: 0.679

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.981

Gnomad4 SAS AF: 0.627

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.459

Alfa AF: 0.413 Hom.: 24060

Bravo AF: 0.532

Asia WGS AF: 0.785 AC: 2729 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800337; hg19: chr16-89845194;