rs11076620

Variant names:

• chr16-89765112-A-T
• rs11076620
• NM_000135.4:c.2602-46T>A

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.2602-46T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0773 in 1,606,892 control chromosomes in the GnomAD database, including 5,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (415 hom., cov: 33)
  • Exomes 𝑓: 0.079 (5338 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.214
• Publications: 6 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=-0.86).
• BP6: Variant 16-89765112-A-T is Benign according to our data. Variant chr16-89765112-A-T is described in ClinVar as Benign. ClinVar VariationId is 255249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 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.2602-46T>A		intron	N/A	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.2602-46T>A		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.2602-46T>A		intron	N/A	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.2602-46T>A		intron	N/A	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.2602-46T>A		intron	N/A	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes AF: 0.0594 AC: 9040 AN: 152070 Hom.: 414 Cov.: 33

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0829

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0672 AC: 16562 AN: 246492 AF XY: 0.0663

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0586

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0773

Gnomad OTH exome AF: 0.0573

GnomAD4 exome AF: 0.0792 AC: 115143 AN: 1454706 Hom.: 5338 Cov.: 29 AF XY: 0.0776 AC XY: 56166 AN XY: 723874

African (AFR) AF: 0.0112 AC: 375 AN: 33352

American (AMR) AF: 0.0212 AC: 942 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 1481 AN: 26048

East Asian (EAS) AF: 0.162 AC: 6412 AN: 39588

South Asian (SAS) AF: 0.0221 AC: 1895 AN: 85628

European-Finnish (FIN) AF: 0.0580 AC: 3084 AN: 53170

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5764

European-Non Finnish (NFE) AF: 0.0867 AC: 95908 AN: 1106728

Other (OTH) AF: 0.0827 AC: 4968 AN: 60098

GnomAD4 genome AF: 0.0594 AC: 9046 AN: 152186 Hom.: 415 Cov.: 33 AF XY: 0.0575 AC XY: 4282 AN XY: 74424

African (AFR) AF: 0.0140 AC: 580 AN: 41570

American (AMR) AF: 0.0376 AC: 575 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 200 AN: 3468

East Asian (EAS) AF: 0.222 AC: 1145 AN: 5164

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4824

European-Finnish (FIN) AF: 0.0606 AC: 643 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0829 AC: 5634 AN: 67948

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0670 Hom.: 61

Bravo AF: 0.0575

Asia WGS AF: 0.113 AC: 391 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.43
DANN	Benign	0.54
PhyloP100		-0.21
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11076620; hg19: chr16-89831520;