rs9879080

Variant names:

• chr3-10042540-C-T
• rs9879080
• NM_001018115.3:c.784-19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):​c.784-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,587,748 control chromosomes in the GnomAD database, including 27,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5011 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22220 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.872
• Publications: 12 publications found

Genes affected

FANCD2 (HGNC:3585): (FA complementation group D2) 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 D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

FANCD2 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group D2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.84).
• BP6: Variant 3-10042540-C-T is Benign according to our data. Variant chr3-10042540-C-T is described in ClinVar as Benign. ClinVar VariationId is 257087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018115.3. 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
	FANCD2	NM_001018115.3	MANE Select	c.784-19C>T		intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.784-19C>T		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.784-19C>T		intron	N/A	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.784-19C>T		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.784-19C>T		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.784-19C>T		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34299 AN: 151946 Hom.: 5005 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0655

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.168 AC: 42343 AN: 251358 AF XY: 0.166

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0654

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.169 AC: 242439 AN: 1435684 Hom.: 22220 Cov.: 27 AF XY: 0.168 AC XY: 120441 AN XY: 715928

African (AFR) AF: 0.430 AC: 14214 AN: 33036

American (AMR) AF: 0.162 AC: 7242 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4073 AN: 25930

East Asian (EAS) AF: 0.0567 AC: 2242 AN: 39550

South Asian (SAS) AF: 0.178 AC: 15256 AN: 85746

European-Finnish (FIN) AF: 0.124 AC: 6617 AN: 53348

Middle Eastern (MID) AF: 0.170 AC: 967 AN: 5698

European-Non Finnish (NFE) AF: 0.167 AC: 181492 AN: 1088182

Other (OTH) AF: 0.174 AC: 10336 AN: 59510

GnomAD4 genome AF: 0.226 AC: 34335 AN: 152064 Hom.: 5011 Cov.: 32 AF XY: 0.220 AC XY: 16341 AN XY: 74332

African (AFR) AF: 0.419 AC: 17362 AN: 41438

American (AMR) AF: 0.155 AC: 2375 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 522 AN: 3470

East Asian (EAS) AF: 0.0655 AC: 339 AN: 5178

South Asian (SAS) AF: 0.161 AC: 778 AN: 4824

European-Finnish (FIN) AF: 0.117 AC: 1237 AN: 10590

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.162 AC: 11030 AN: 67974

Other (OTH) AF: 0.194 AC: 410 AN: 2114

Alfa AF: 0.195 Hom.: 667

Bravo AF: 0.240

Asia WGS AF: 0.124 AC: 435 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group D2 (3)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.4
DANN	Benign	0.50
PhyloP100		0.87
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: rs9879080; hg19: chr3-10084224; COSMIC: COSV55047416;