rs1800330

chr16-89791556-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.1226-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,612,996 control chromosomes in the GnomAD database, including 123,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15206 hom., cov: 32)
  • Exomes 𝑓: 0.37 (108522 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.44

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=-0.94).
• BP6: Variant 16-89791556-T-C is Benign according to our data. Variant chr16-89791556-T-C is described in ClinVar as [Benign]. Clinvar id is 255232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89791556-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.1226-20A>G		intron_variant		ENST00000389301.8
FANCA	NM_001286167.3	c.1226-20A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.1226-20A>G		intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64622 AN: 151940 Hom.: 15190 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.765

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.441 AC: 109976 AN: 249494 Hom.: 27758 AF XY: 0.433 AC XY: 58432 AN XY: 134936

Gnomad AFR exome AF: 0.560

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.753

Gnomad SAS exome AF: 0.567

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.367 AC: 535470 AN: 1460938 Hom.: 108522 Cov.: 47 AF XY: 0.370 AC XY: 268844 AN XY: 726768

Gnomad4 AFR exome AF: 0.562

Gnomad4 AMR exome AF: 0.620

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.824

Gnomad4 SAS exome AF: 0.565

Gnomad4 FIN exome AF: 0.400

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.425 AC: 64691 AN: 152058 Hom.: 15206 Cov.: 32 AF XY: 0.438 AC XY: 32581 AN XY: 74318

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.381

Alfa AF: 0.337 Hom.: 8741

Bravo AF: 0.438

Asia WGS AF: 0.665 AC: 2312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.10
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800330; hg19: chr16-89857964; COSMIC: COSV66881251; COSMIC: COSV66881251;