rs17232616

Variant names:

• chr16-89784971-G-A
• rs17232616
• NM_000135.4:c.1360-7C>T

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.1360-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,608,154 control chromosomes in the GnomAD database, including 371 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 0.028 (193 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (178 hom.)
• Consequence: FANCA NM_000135.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002991
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.24
• Publications: 1 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=-0.81).
• BP6: Variant 16-89784971-G-A is Benign according to our data. Variant chr16-89784971-G-A is described in ClinVar as Benign. ClinVar VariationId is 321359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0952 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.1360-7C>T		splice_region intron	N/A	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.1360-7C>T		splice_region 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.1360-7C>T		splice_region intron	N/A	ENSP00000373952.3	O15360-1
	FANCA	ENST00000567205.2	TSL:1	n.1360-7C>T		splice_region intron	N/A	ENSP00000457027.2	H3BT53
	FANCA	ENST00000564475.6	TSL:2	c.1360-7C>T		splice_region intron	N/A	ENSP00000454977.2	H3BNS0

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4255 AN: 152112 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00734 AC: 1843 AN: 251042 AF XY: 0.00553

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00285 AC: 4145 AN: 1455924 Hom.: 178 Cov.: 29 AF XY: 0.00247 AC XY: 1790 AN XY: 724690

African (AFR) AF: 0.102 AC: 3405 AN: 33320

American (AMR) AF: 0.00523 AC: 234 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5756

European-Non Finnish (NFE) AF: 0.0000940 AC: 104 AN: 1106882

Other (OTH) AF: 0.00605 AC: 364 AN: 60148

GnomAD4 genome AF: 0.0280 AC: 4261 AN: 152230 Hom.: 193 Cov.: 32 AF XY: 0.0279 AC XY: 2076 AN XY: 74436

African (AFR) AF: 0.0977 AC: 4055 AN: 41516

American (AMR) AF: 0.0103 AC: 157 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0145 Hom.: 52

Bravo AF: 0.0318

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group A (4)
-	-	3	not provided (3)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.57
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
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: rs17232616; hg19: chr16-89851379;