rs1800345

Variant names:

• chr16-89748809-C-T
• rs1800345
• NM_000135.4:c.3240-42G>A

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.3240-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,519,736 control chromosomes in the GnomAD database, including 110,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14368 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95672 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.715
• Publications: 17 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: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health
• 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=-0.89).
• BP6: Variant 16-89748809-C-T is Benign according to our data. Variant chr16-89748809-C-T is described in ClinVar as Benign. ClinVar VariationId is 255254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.3240-42G>A		intron	N/A	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.3240-42G>A		intron	N/A	NP_001273096.1	O15360-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3240-42G>A		intron	N/A	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.3240-42G>A		intron	N/A	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.3240-42G>A		intron	N/A	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62790 AN: 151836 Hom.: 14350 Cov.: 32

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.367

GnomAD2 exomes AF: 0.428 AC: 93476 AN: 218474 AF XY: 0.417

Gnomad AFR exome AF: 0.555

Gnomad AMR exome AF: 0.631

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.753

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.374

GnomAD4 exome AF: 0.357 AC: 488030 AN: 1367782 Hom.: 95672 Cov.: 20 AF XY: 0.358 AC XY: 244329 AN XY: 683166

African (AFR) AF: 0.551 AC: 17586 AN: 31914

American (AMR) AF: 0.611 AC: 25259 AN: 41314

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6264 AN: 25306

East Asian (EAS) AF: 0.818 AC: 31775 AN: 38838

South Asian (SAS) AF: 0.479 AC: 39736 AN: 82954

European-Finnish (FIN) AF: 0.392 AC: 20008 AN: 51100

Middle Eastern (MID) AF: 0.272 AC: 1469 AN: 5410

European-Non Finnish (NFE) AF: 0.315 AC: 325285 AN: 1033686

Other (OTH) AF: 0.361 AC: 20648 AN: 57260

GnomAD4 genome AF: 0.414 AC: 62862 AN: 151954 Hom.: 14368 Cov.: 32 AF XY: 0.425 AC XY: 31581 AN XY: 74242

African (AFR) AF: 0.542 AC: 22484 AN: 41446

American (AMR) AF: 0.489 AC: 7471 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 852 AN: 3472

East Asian (EAS) AF: 0.757 AC: 3898 AN: 5146

South Asian (SAS) AF: 0.496 AC: 2385 AN: 4808

European-Finnish (FIN) AF: 0.400 AC: 4224 AN: 10550

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20447 AN: 67946

Other (OTH) AF: 0.373 AC: 786 AN: 2110

Alfa AF: 0.345 Hom.: 1904

Bravo AF: 0.430

Asia WGS AF: 0.615 AC: 2137 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia complementation group A (2)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.22
DANN	Benign	0.53
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800345; hg19: chr16-89815217;