3-10096505-T-C

Variant names:

• chr3-10096505-T-C
• rs2272124
• NM_001018115.3:c.4185+33T>C

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.4185+33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,605,722 control chromosomes in the GnomAD database, including 29,771 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5948 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23823 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0720
• Publications: 19 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=-0.9).
• BP6: Variant 3-10096505-T-C is Benign according to our data. Variant chr3-10096505-T-C is described in ClinVar as Benign. ClinVar VariationId is 257082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 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.4185+33T>C		intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.4185+33T>C		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.4146+33T>C		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.4185+33T>C		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.4185+33T>C		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.4185+33T>C		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36724 AN: 151938 Hom.: 5940 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0895

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.206

GnomAD2 exomes AF: 0.181 AC: 45324 AN: 251020 AF XY: 0.178

Gnomad AFR exome AF: 0.478

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0894

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.172 AC: 250292 AN: 1453666 Hom.: 23823 Cov.: 29 AF XY: 0.172 AC XY: 124498 AN XY: 723598

African (AFR) AF: 0.474 AC: 15742 AN: 33238

American (AMR) AF: 0.186 AC: 8298 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4091 AN: 26086

East Asian (EAS) AF: 0.0758 AC: 3007 AN: 39662

South Asian (SAS) AF: 0.209 AC: 18037 AN: 86100

European-Finnish (FIN) AF: 0.123 AC: 6579 AN: 53334

Middle Eastern (MID) AF: 0.171 AC: 981 AN: 5740

European-Non Finnish (NFE) AF: 0.165 AC: 182700 AN: 1104730

Other (OTH) AF: 0.181 AC: 10857 AN: 60090

GnomAD4 genome AF: 0.242 AC: 36761 AN: 152056 Hom.: 5948 Cov.: 32 AF XY: 0.236 AC XY: 17568 AN XY: 74356

African (AFR) AF: 0.463 AC: 19182 AN: 41424

American (AMR) AF: 0.173 AC: 2644 AN: 15264

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

East Asian (EAS) AF: 0.0894 AC: 462 AN: 5170

South Asian (SAS) AF: 0.201 AC: 971 AN: 4822

European-Finnish (FIN) AF: 0.116 AC: 1230 AN: 10594

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11032 AN: 67998

Other (OTH) AF: 0.206 AC: 434 AN: 2108

Alfa AF: 0.187 Hom.: 4227

Bravo AF: 0.258

Asia WGS AF: 0.147 AC: 512 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fanconi anemia complementation group D2 (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	-0.90
CADD	Benign	2.8
DANN	Benign	0.60
PhyloP100		-0.072
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)		0.030		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: rs2272124; hg19: chr3-10138189; COSMIC: COSV55047440;