16-89771670-A-G

Variant names:

• chr16-89771670-A-G
• rs1800340
• NM_000135.4:c.2151+8T>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.2151+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,613,336 control chromosomes in the GnomAD database, including 121,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14251 hom., cov: 31)
  • Exomes 𝑓: 0.37 (107601 hom.)
• Consequence: FANCA NM_000135.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001916
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.39
• Publications: 22 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=-0.9).
• BP6: Variant 16-89771670-A-G is Benign according to our data. Variant chr16-89771670-A-G is described in ClinVar as Benign. ClinVar VariationId is 255245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 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.2151+8T>C		splice_region intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.2151+8T>C		splice_region 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.2151+8T>C		splice_region intron	N/A	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.2151+8T>C		splice_region intron	N/A	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.2151+8T>C		splice_region intron	N/A	ENSP00000454977.2

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62868 AN: 151740 Hom.: 14233 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.438 AC: 110023 AN: 251442 AF XY: 0.431

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.743

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.365 AC: 533872 AN: 1461478 Hom.: 107601 Cov.: 39 AF XY: 0.369 AC XY: 268195 AN XY: 727066

African (AFR) AF: 0.521 AC: 17445 AN: 33468

American (AMR) AF: 0.618 AC: 27621 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6958 AN: 26136

East Asian (EAS) AF: 0.817 AC: 32433 AN: 39696

South Asian (SAS) AF: 0.568 AC: 48976 AN: 86252

European-Finnish (FIN) AF: 0.405 AC: 21628 AN: 53386

Middle Eastern (MID) AF: 0.308 AC: 1778 AN: 5764

European-Non Finnish (NFE) AF: 0.319 AC: 354632 AN: 1111672

Other (OTH) AF: 0.371 AC: 22401 AN: 60382

GnomAD4 genome AF: 0.414 AC: 62938 AN: 151858 Hom.: 14251 Cov.: 31 AF XY: 0.428 AC XY: 31765 AN XY: 74214

African (AFR) AF: 0.514 AC: 21280 AN: 41412

American (AMR) AF: 0.487 AC: 7433 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 937 AN: 3464

East Asian (EAS) AF: 0.753 AC: 3882 AN: 5152

South Asian (SAS) AF: 0.598 AC: 2868 AN: 4796

European-Finnish (FIN) AF: 0.410 AC: 4315 AN: 10524

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21113 AN: 67936

Other (OTH) AF: 0.374 AC: 790 AN: 2112

Alfa AF: 0.357 Hom.: 7293

Bravo AF: 0.425

Asia WGS AF: 0.654 AC: 2273 AN: 3478

EpiCase AF: 0.306

EpiControl AF: 0.294

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Fanconi anemia complementation group A (6)
-	-	1	Fanconi anemia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.017
DANN	Benign	0.49
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs1800340; hg19: chr16-89838078; COSMIC: COSV66881670; COSMIC: COSV66881670;