16-89792117-C-G

Variant names:

• chr16-89792117-C-G
• rs1800287
• NM_000135.4:c.1084-49G>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.1084-49G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,610,850 control chromosomes in the GnomAD database, including 184,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (24632 hom., cov: 32)
  • Exomes 𝑓: 0.45 (159580 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.109
• Publications: 18 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=-0.89).
• BP6: Variant 16-89792117-C-G is Benign according to our data. Variant chr16-89792117-C-G is described in ClinVar as Benign. ClinVar VariationId is 255230.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.1084-49G>C		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.1084-49G>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.1084-49G>C		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.1084-49G>C		intron	N/A	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.1084-49G>C		intron	N/A	ENSP00000454977.2

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81801 AN: 151958 Hom.: 24598 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.521 AC: 130698 AN: 250854 AF XY: 0.508

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.665

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.984

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.451 AC: 657426 AN: 1458778 Hom.: 159580 Cov.: 33 AF XY: 0.452 AC XY: 327870 AN XY: 725948

African (AFR) AF: 0.761 AC: 25435 AN: 33436

American (AMR) AF: 0.650 AC: 29063 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 8298 AN: 26116

East Asian (EAS) AF: 0.980 AC: 38895 AN: 39688

South Asian (SAS) AF: 0.587 AC: 50637 AN: 86196

European-Finnish (FIN) AF: 0.458 AC: 24375 AN: 53224

Middle Eastern (MID) AF: 0.338 AC: 1944 AN: 5758

European-Non Finnish (NFE) AF: 0.406 AC: 450589 AN: 1109392

Other (OTH) AF: 0.468 AC: 28190 AN: 60268

GnomAD4 genome AF: 0.539 AC: 81896 AN: 152072 Hom.: 24632 Cov.: 32 AF XY: 0.548 AC XY: 40687 AN XY: 74314

African (AFR) AF: 0.751 AC: 31139 AN: 41478

American (AMR) AF: 0.546 AC: 8345 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5085 AN: 5184

South Asian (SAS) AF: 0.624 AC: 3011 AN: 4822

European-Finnish (FIN) AF: 0.469 AC: 4951 AN: 10550

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26888 AN: 67964

Other (OTH) AF: 0.476 AC: 1007 AN: 2114

Alfa AF: 0.443 Hom.: 2997

Bravo AF: 0.556

ClinVar

ClinVar submissions as Germline

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800287; hg19: chr16-89858525; COSMIC: COSV66881254;