3-10048089-A-C

Variant names:

• chr3-10048089-A-C
• rs7615646
• NM_001018115.3:c.1413+38A>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.1413+38A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,556,388 control chromosomes in the GnomAD database, including 3,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (217 hom., cov: 47)
  • Exomes 𝑓: 0.12 (2830 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.402
• Publications: 18 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 3-10048089-A-C is Benign according to our data. Variant chr3-10048089-A-C is described in ClinVar as Benign. ClinVar VariationId is 257067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.1413+38A>C		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.1413+38A>C		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.1413+38A>C		intron	N/A	NP_001361183.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.1413+38A>C		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.1413+38A>C		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.1413+38A>C		intron	N/A	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16222 AN: 150984 Hom.: 217 Cov.: 47

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0914

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.0430

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.0769

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.0952

GnomAD2 exomes AF: 0.220 AC: 31970 AN: 145128 AF XY: 0.225

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.119 AC: 166639 AN: 1405282 Hom.: 2830 Cov.: 44 AF XY: 0.117 AC XY: 82302 AN XY: 700940

African (AFR) AF: 0.205 AC: 6638 AN: 32430

American (AMR) AF: 0.109 AC: 4812 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 2566 AN: 25676

East Asian (EAS) AF: 0.0381 AC: 1494 AN: 39228

South Asian (SAS) AF: 0.127 AC: 10761 AN: 84780

European-Finnish (FIN) AF: 0.0705 AC: 3705 AN: 52578

Middle Eastern (MID) AF: 0.104 AC: 583 AN: 5598

European-Non Finnish (NFE) AF: 0.122 AC: 129464 AN: 1062262

Other (OTH) AF: 0.113 AC: 6616 AN: 58396

GnomAD4 genome AF: 0.107 AC: 16242 AN: 151106 Hom.: 217 Cov.: 47 AF XY: 0.104 AC XY: 7713 AN XY: 73868

African (AFR) AF: 0.165 AC: 6782 AN: 41084

American (AMR) AF: 0.0911 AC: 1387 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 306 AN: 3436

East Asian (EAS) AF: 0.0429 AC: 222 AN: 5176

South Asian (SAS) AF: 0.107 AC: 513 AN: 4786

European-Finnish (FIN) AF: 0.0657 AC: 693 AN: 10542

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.0884 AC: 5974 AN: 67574

Other (OTH) AF: 0.0951 AC: 199 AN: 2092

Alfa AF: 0.162 Hom.: 994

Bravo AF: 0.205

Asia WGS AF: 0.113 AC: 395 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 D2 (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.5
DANN	Benign	0.53
PhyloP100		0.40
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: rs7615646; hg19: chr3-10089773;