16-89746786-C-T

Variant names:

• chr16-89746786-C-T
• rs1800355
• NM_000135.4:c.3408+45G>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.3408+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,578,520 control chromosomes in the GnomAD database, including 5,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (416 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5219 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.15
• Publications: 9 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=-0.93).
• BP6: Variant 16-89746786-C-T is Benign according to our data. Variant chr16-89746786-C-T is described in ClinVar as Benign. ClinVar VariationId is 255259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.3408+45G>A		intron_variant	Intron 34 of 42	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.3408+45G>A		intron_variant	Intron 34 of 42		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.3408+45G>A		intron_variant	Intron 34 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9057 AN: 152102 Hom.: 415 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0616

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0834

Gnomad OTH AF: 0.0560

GnomAD2 exomes AF: 0.0683 AC: 13473 AN: 197154 AF XY: 0.0680

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0574

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.0617

Gnomad NFE exome AF: 0.0807

Gnomad OTH exome AF: 0.0575

GnomAD4 exome AF: 0.0794 AC: 113278 AN: 1426300 Hom.: 5219 Cov.: 30 AF XY: 0.0780 AC XY: 55144 AN XY: 707294

African (AFR) AF: 0.0112 AC: 364 AN: 32590

American (AMR) AF: 0.0217 AC: 851 AN: 39194

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 1443 AN: 25546

East Asian (EAS) AF: 0.155 AC: 5919 AN: 38070

South Asian (SAS) AF: 0.0221 AC: 1834 AN: 82984

European-Finnish (FIN) AF: 0.0582 AC: 3004 AN: 51602

Middle Eastern (MID) AF: 0.0131 AC: 75 AN: 5718

European-Non Finnish (NFE) AF: 0.0869 AC: 94875 AN: 1091446

Other (OTH) AF: 0.0831 AC: 4913 AN: 59150

GnomAD4 genome AF: 0.0595 AC: 9064 AN: 152220 Hom.: 416 Cov.: 32 AF XY: 0.0575 AC XY: 4279 AN XY: 74416

African (AFR) AF: 0.0140 AC: 582 AN: 41562

American (AMR) AF: 0.0374 AC: 572 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3468

East Asian (EAS) AF: 0.217 AC: 1120 AN: 5166

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4822

European-Finnish (FIN) AF: 0.0616 AC: 652 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0833 AC: 5668 AN: 68004

Other (OTH) AF: 0.0563 AC: 119 AN: 2112

Alfa AF: 0.0683 Hom.: 108

Bravo AF: 0.0572

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group A Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.31
DANN	Benign	0.50
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1800355; hg19: chr16-89813194; COSMIC: COSV59795594;