chr16-89742763-C-T

Variant names:

• chr16-89742763-C-T
• rs34420680
• NM_000135.4:c.3765+37G>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.3765+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 1,607,346 control chromosomes in the GnomAD database, including 5,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (410 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5300 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.721
• Publications: 10 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: ClinGen, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.89).
• BP6: Variant 16-89742763-C-T is Benign according to our data. Variant chr16-89742763-C-T is described in ClinVar as Benign. ClinVar VariationId is 255262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 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.3765+37G>A		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.3765+37G>A		intron	N/A	NP_001273096.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3765+37G>A		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000564475.6	TSL:2	c.3765+37G>A		intron	N/A	ENSP00000454977.2
	FANCA	ENST00000568369.6	TSL:2	c.3765+37G>A		intron	N/A	ENSP00000456829.1

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9024 AN: 151556 Hom.: 409 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.0264

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.0565

GnomAD2 exomes AF: 0.0665 AC: 16690 AN: 251094 AF XY: 0.0657

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0584

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.0586

Gnomad NFE exome AF: 0.0766

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0788 AC: 114709 AN: 1455694 Hom.: 5300 Cov.: 31 AF XY: 0.0773 AC XY: 55979 AN XY: 724286

African (AFR) AF: 0.0113 AC: 375 AN: 33198

American (AMR) AF: 0.0211 AC: 940 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0572 AC: 1483 AN: 25940

East Asian (EAS) AF: 0.158 AC: 6215 AN: 39338

South Asian (SAS) AF: 0.0220 AC: 1893 AN: 85990

European-Finnish (FIN) AF: 0.0576 AC: 3037 AN: 52716

Middle Eastern (MID) AF: 0.0133 AC: 76 AN: 5734

European-Non Finnish (NFE) AF: 0.0864 AC: 95755 AN: 1108236

Other (OTH) AF: 0.0823 AC: 4935 AN: 59960

GnomAD4 genome AF: 0.0596 AC: 9031 AN: 151652 Hom.: 410 Cov.: 32 AF XY: 0.0575 AC XY: 4257 AN XY: 74056

African (AFR) AF: 0.0141 AC: 581 AN: 41308

American (AMR) AF: 0.0372 AC: 567 AN: 15230

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

East Asian (EAS) AF: 0.218 AC: 1123 AN: 5140

South Asian (SAS) AF: 0.0273 AC: 131 AN: 4804

European-Finnish (FIN) AF: 0.0612 AC: 640 AN: 10450

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0831 AC: 5646 AN: 67948

Other (OTH) AF: 0.0570 AC: 120 AN: 2106

Alfa AF: 0.0430 Hom.: 40

Bravo AF: 0.0572

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.65
PhyloP100		-0.72
PromoterAI		0.019	Neutral
Mutation Taster		=100/0	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: rs34420680; hg19: chr16-89809171; COSMIC: COSV57066225; COSMIC: COSV57066225;