chr16-89778770-T-TAC

Variant names:

• chr16-89778770-T-TAC
• rs36204974
• NM_000135.4:c.1826+30_1826+31insGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.1826+30_1826+31insGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0743 in 1,598,144 control chromosomes in the GnomAD database, including 5,628 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (423 hom., cov: 30)
  • Exomes 𝑓: 0.076 (5205 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.384
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 16-89778770-T-TAC is Benign according to our data. Variant chr16-89778770-T-TAC is described in ClinVar as Benign. ClinVar VariationId is 255242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.1826+30_1826+31insGT		intron_variant	Intron 20 of 42	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.1826+30_1826+31insGT		intron_variant	Intron 20 of 42		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.1826+30_1826+31insGT		intron_variant	Intron 20 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9086 AN: 151442 Hom.: 422 Cov.: 30

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.0262

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0549

GnomAD2 exomes AF: 0.0673 AC: 16922 AN: 251406 AF XY: 0.0664

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0587

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0758 AC: 109648 AN: 1446584 Hom.: 5205 Cov.: 29 AF XY: 0.0746 AC XY: 53766 AN XY: 720868

African (AFR) AF: 0.0111 AC: 367 AN: 33152

American (AMR) AF: 0.0212 AC: 949 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 1465 AN: 26068

East Asian (EAS) AF: 0.161 AC: 6358 AN: 39564

South Asian (SAS) AF: 0.0219 AC: 1879 AN: 85956

European-Finnish (FIN) AF: 0.0571 AC: 3047 AN: 53390

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5754

European-Non Finnish (NFE) AF: 0.0826 AC: 90705 AN: 1098140

Other (OTH) AF: 0.0803 AC: 4805 AN: 59852

GnomAD4 genome AF: 0.0600 AC: 9092 AN: 151560 Hom.: 423 Cov.: 30 AF XY: 0.0580 AC XY: 4296 AN XY: 74006

African (AFR) AF: 0.0140 AC: 578 AN: 41298

American (AMR) AF: 0.0380 AC: 576 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3464

East Asian (EAS) AF: 0.226 AC: 1164 AN: 5148

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4812

European-Finnish (FIN) AF: 0.0617 AC: 642 AN: 10408

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0833 AC: 5663 AN: 67960

Other (OTH) AF: 0.0552 AC: 116 AN: 2100

Alfa AF: 0.0684 Hom.: 76

Bravo AF: 0.0576

Asia WGS AF: 0.115 AC: 400 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs36204974; hg19: chr16-89845178;