16-89778786-A-G

Variant names:

• chr16-89778786-A-G
• rs1800337
• NM_000135.4:c.1826+15T>C

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.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:9
• Conservation: PhyloP100: -1.36
• Publications: 28 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: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• 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=-0.91).
• BP6: Variant 16-89778786-A-G is Benign according to our data. Variant chr16-89778786-A-G is described in ClinVar as Benign. ClinVar VariationId is 255241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.1826+15T>C		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.1826+15T>C		intron	N/A	NP_001273096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.1826+15T>C		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.1826+15T>C		intron	N/A	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.1826+15T>C		intron	N/A	ENSP00000454977.2

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

GnomAD2 exomes AF: 0.516 AC: 129841 AN: 251404 AF XY: 0.505

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 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

African (AFR) AF: 0.691 AC: 23093 AN: 33420

American (AMR) AF: 0.647 AC: 28921 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8432 AN: 26112

East Asian (EAS) AF: 0.980 AC: 38889 AN: 39682

South Asian (SAS) AF: 0.591 AC: 50896 AN: 86176

European-Finnish (FIN) AF: 0.464 AC: 24781 AN: 53396

Middle Eastern (MID) AF: 0.330 AC: 1897 AN: 5754

European-Non Finnish (NFE) AF: 0.405 AC: 448762 AN: 1107220

Other (OTH) AF: 0.463 AC: 27908 AN: 60226

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

African (AFR) AF: 0.679 AC: 28104 AN: 41398

American (AMR) AF: 0.539 AC: 8218 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1135 AN: 3468

East Asian (EAS) AF: 0.981 AC: 5075 AN: 5174

South Asian (SAS) AF: 0.627 AC: 3022 AN: 4816

European-Finnish (FIN) AF: 0.474 AC: 4994 AN: 10528

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26800 AN: 67944

Other (OTH) AF: 0.459 AC: 965 AN: 2104

Alfa AF: 0.433 Hom.: 60388

Bravo AF: 0.532

Asia WGS AF: 0.785 AC: 2729 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fanconi anemia complementation group A (5)
-	-	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	-0.91
CADD	Benign	1.5
DANN	Benign	0.32
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800337; hg19: chr16-89845194;