chr16-89778789-G-A

Variant names:

• chr16-89778789-G-A
• rs183513839
• NM_000135.4:c.1826+12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):​c.1826+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,613,028 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (41 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.44
• Publications: 4 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=-0.96).
• BP6: Variant 16-89778789-G-A is Benign according to our data. Variant chr16-89778789-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00513 (780/152144) while in subpopulation AMR AF = 0.00872 (133/15252). AF 95% confidence interval is 0.00751. There are 2 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1826+12C>T		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.1826+12C>T		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.1826+12C>T		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.1826+12C>T		intron	N/A	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.1826+12C>T		intron	N/A	ENSP00000454977.2

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 781 AN: 152028 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00873

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00928

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00603 AC: 1516 AN: 251484 AF XY: 0.00641

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00942

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00672 AC: 9816 AN: 1460884 Hom.: 41 Cov.: 34 AF XY: 0.00663 AC XY: 4820 AN XY: 726836

African (AFR) AF: 0.00111 AC: 37 AN: 33458

American (AMR) AF: 0.00396 AC: 177 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00553 AC: 477 AN: 86222

European-Finnish (FIN) AF: 0.0100 AC: 534 AN: 53416

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00740 AC: 8220 AN: 1111102

Other (OTH) AF: 0.00578 AC: 349 AN: 60368

GnomAD4 genome AF: 0.00513 AC: 780 AN: 152144 Hom.: 2 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74374

African (AFR) AF: 0.00140 AC: 58 AN: 41542

American (AMR) AF: 0.00872 AC: 133 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.00928 AC: 98 AN: 10556

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68010

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00544 Hom.: 0

Bravo AF: 0.00518

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group A (3)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.18
DANN	Benign	0.40
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs183513839; hg19: chr16-89845197;