NM_001018115.3:c.3849+13A>G

Variant names:

• chr3-10092265-A-G
• rs9811771
• NM_001018115.3:c.3849+13A>G

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.3849+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,588,626 control chromosomes in the GnomAD database, including 30,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6451 hom., cov: 30)
  • Exomes 𝑓: 0.17 (24273 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.730
• Publications: 16 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]

FANCD2OS (HGNC:28623): (FANCD2 opposite strand) This gene encodes a conserved protein of unknown function. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 3-10092265-A-G is Benign according to our data. Variant chr3-10092265-A-G is described in ClinVar as Benign. ClinVar VariationId is 257079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 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.3849+13A>G		intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.3849+13A>G		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.3849+13A>G		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.3849+13A>G		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.3849+13A>G		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.3849+13A>G		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37805 AN: 151804 Hom.: 6440 Cov.: 30

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0893

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.185 AC: 46335 AN: 251018 AF XY: 0.182

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0893

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.174 AC: 249645 AN: 1436704 Hom.: 24273 Cov.: 27 AF XY: 0.174 AC XY: 124831 AN XY: 716414

African (AFR) AF: 0.500 AC: 16427 AN: 32886

American (AMR) AF: 0.187 AC: 8338 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 4062 AN: 25974

East Asian (EAS) AF: 0.0757 AC: 2994 AN: 39572

South Asian (SAS) AF: 0.227 AC: 19485 AN: 85754

European-Finnish (FIN) AF: 0.123 AC: 6576 AN: 53264

Middle Eastern (MID) AF: 0.190 AC: 1085 AN: 5702

European-Non Finnish (NFE) AF: 0.165 AC: 179729 AN: 1089298

Other (OTH) AF: 0.184 AC: 10949 AN: 59562

GnomAD4 genome AF: 0.249 AC: 37854 AN: 151922 Hom.: 6451 Cov.: 30 AF XY: 0.243 AC XY: 18064 AN XY: 74262

African (AFR) AF: 0.486 AC: 20113 AN: 41382

American (AMR) AF: 0.176 AC: 2692 AN: 15260

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

East Asian (EAS) AF: 0.0891 AC: 461 AN: 5172

South Asian (SAS) AF: 0.220 AC: 1057 AN: 4812

European-Finnish (FIN) AF: 0.116 AC: 1224 AN: 10558

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11046 AN: 67952

Other (OTH) AF: 0.214 AC: 451 AN: 2110

Alfa AF: 0.197 Hom.: 10037

Bravo AF: 0.266

Asia WGS AF: 0.158 AC: 550 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	-0.72
CADD	Benign	15
DANN	Benign	0.86
PhyloP100		0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs9811771; hg19: chr3-10133949; COSMIC: COSV55047434;