rs9809716

Variant names:

• chr3-10064831-T-C
• rs9809716
• NM_001018115.3:c.2124T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001018115.3(FANCD2):​c.2124T>C​(p.Phe708Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,613,774 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (92 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (56 hom.)
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.150
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-10064831-T-C is Benign according to our data. Variant chr3-10064831-T-C is described in ClinVar as Benign. ClinVar VariationId is 257072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0865 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.2124T>C	p.Phe708Phe	synonymous	Exon 23 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.2124T>C	p.Phe708Phe	synonymous	Exon 23 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.2124T>C	p.Phe708Phe	synonymous	Exon 23 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.2124T>C	p.Phe708Phe	synonymous	Exon 23 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.2124T>C	p.Phe708Phe	synonymous	Exon 23 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.2124T>C	p.Phe708Phe	synonymous	Exon 23 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3881 AN: 152106 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00904

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00637 AC: 1600 AN: 251166 AF XY: 0.00454

Gnomad AFR exome AF: 0.0892

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00245 AC: 3574 AN: 1461550 Hom.: 56 Cov.: 33 AF XY: 0.00212 AC XY: 1544 AN XY: 727108

African (AFR) AF: 0.0866 AC: 2894 AN: 33432

American (AMR) AF: 0.00418 AC: 187 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5760

European-Non Finnish (NFE) AF: 0.000131 AC: 146 AN: 1111766

Other (OTH) AF: 0.00545 AC: 329 AN: 60376

GnomAD4 genome AF: 0.0255 AC: 3887 AN: 152224 Hom.: 92 Cov.: 33 AF XY: 0.0247 AC XY: 1840 AN XY: 74420

African (AFR) AF: 0.0889 AC: 3686 AN: 41472

American (AMR) AF: 0.00902 AC: 138 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68030

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0136 Hom.: 21

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.7
DANN	Benign	0.37
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9809716; hg19: chr3-10106515;