rs6500452

chr16-89792097-T-C

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.1084-29A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,613,442 control chromosomes in the GnomAD database, including 113,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13553 hom., cov: 32)
  • Exomes 𝑓: 0.35 (99939 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.08

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=-0.89).
• BP6: Variant 16-89792097-T-C is Benign according to our data. Variant chr16-89792097-T-C is described in ClinVar as [Benign]. Clinvar id is 255229.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.1084-29A>G		intron_variant		ENST00000389301.8
FANCA	NM_001286167.3	c.1084-29A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.1084-29A>G		intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61237 AN: 151942 Hom.: 13540 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.355

GnomAD3 exomes AF: 0.418 AC: 105168 AN: 251304 Hom.: 25385 AF XY: 0.408 AC XY: 55378 AN XY: 135854

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.631

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.749

Gnomad SAS exome AF: 0.478

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.353 AC: 515280 AN: 1461382 Hom.: 99939 Cov.: 39 AF XY: 0.354 AC XY: 257151 AN XY: 727024

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.612

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.816

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.388

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome AF: 0.403 AC: 61295 AN: 152060 Hom.: 13553 Cov.: 32 AF XY: 0.415 AC XY: 30867 AN XY: 74324

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.479

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.759

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.361

Alfa AF: 0.333 Hom.: 5400

Bravo AF: 0.417

Asia WGS AF: 0.613 AC: 2133 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fanconi anemia complementation group A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.096
Dann	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6500452; hg19: chr16-89858505; COSMIC: COSV66880734; COSMIC: COSV66880734;