16-89803353-T-C

Variant names:

• chr16-89803353-T-C
• rs1800286
• NM_000135.4:c.710-12A>G

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.710-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 1,612,118 control chromosomes in the GnomAD database, including 350,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (41010 hom., cov: 32)
  • Exomes 𝑓: 0.64 (309565 hom.)
• Consequence: FANCA NM_000135.4 intron
• Scores: Splicing: ADA: 0.0001637
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.95
• Publications: 29 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=-0.72).
• BP6: Variant 16-89803353-T-C is Benign according to our data. Variant chr16-89803353-T-C is described in ClinVar as Benign. ClinVar VariationId is 255269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 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.710-12A>G		intron	N/A	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.710-12A>G		intron	N/A	NP_001273096.1	O15360-3
	FANCA	NM_001018112.3		c.710-12A>G		intron	N/A	NP_001018122.1	O15360-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.710-12A>G		intron	N/A	ENSP00000373952.3	O15360-1
	FANCA	ENST00000563673.5	TSL:1	c.710-12A>G		intron	N/A	ENSP00000456443.1	H3BRX3
	FANCA	ENST00000534992.5	TSL:1	c.710-12A>G		intron	N/A	ENSP00000443675.1	F5H8D5

Frequencies

GnomAD3 genomes AF: 0.717 AC: 109012 AN: 151996 Hom.: 40949 Cov.: 32

Gnomad AFR AF: 0.917

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.815

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.665

GnomAD2 exomes AF: 0.699 AC: 175544 AN: 251232 AF XY: 0.692

Gnomad AFR exome AF: 0.923

Gnomad AMR exome AF: 0.783

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.989

Gnomad FIN exome AF: 0.680

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.642

GnomAD4 exome AF: 0.644 AC: 940548 AN: 1460004 Hom.: 309565 Cov.: 34 AF XY: 0.647 AC XY: 469764 AN XY: 726362

African (AFR) AF: 0.926 AC: 30963 AN: 33442

American (AMR) AF: 0.773 AC: 34567 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 13687 AN: 26112

East Asian (EAS) AF: 0.983 AC: 38992 AN: 39686

South Asian (SAS) AF: 0.796 AC: 68658 AN: 86234

European-Finnish (FIN) AF: 0.670 AC: 35782 AN: 53372

Middle Eastern (MID) AF: 0.651 AC: 3755 AN: 5766

European-Non Finnish (NFE) AF: 0.608 AC: 674720 AN: 1110346

Other (OTH) AF: 0.653 AC: 39424 AN: 60334

GnomAD4 genome AF: 0.717 AC: 109134 AN: 152114 Hom.: 41010 Cov.: 32 AF XY: 0.725 AC XY: 53920 AN XY: 74338

African (AFR) AF: 0.917 AC: 38081 AN: 41546

American (AMR) AF: 0.695 AC: 10603 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1799 AN: 3470

East Asian (EAS) AF: 0.986 AC: 5110 AN: 5180

South Asian (SAS) AF: 0.815 AC: 3936 AN: 4832

European-Finnish (FIN) AF: 0.676 AC: 7139 AN: 10554

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40443 AN: 67960

Other (OTH) AF: 0.669 AC: 1412 AN: 2112

Alfa AF: 0.627 Hom.: 19456

Bravo AF: 0.729

Asia WGS AF: 0.900 AC: 3131 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fanconi anemia complementation group A (5)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.5
DANN	Benign	0.79
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.040
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: rs1800286; hg19: chr16-89869761;