NM_001018115.3:c.2269+37A>G

Variant names:

• chr3-10065531-A-G
• rs34323624
• NM_001018115.3:c.2269+37A>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.2269+37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,369,090 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (245 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (181 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.623
• Publications: 2 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=-0.82).
• BP6: Variant 3-10065531-A-G is Benign according to our data. Variant chr3-10065531-A-G is described in ClinVar as Benign. ClinVar VariationId is 257073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 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.2269+37A>G		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.2269+37A>G		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.2269+37A>G		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.2269+37A>G		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.2269+37A>G		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.2269+37A>G		intron	N/A	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4657 AN: 151734 Hom.: 239 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0235

GnomAD2 exomes AF: 0.00768 AC: 1931 AN: 251368 AF XY: 0.00554

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00308 AC: 3744 AN: 1217238 Hom.: 181 Cov.: 17 AF XY: 0.00267 AC XY: 1650 AN XY: 617494

African (AFR) AF: 0.104 AC: 2962 AN: 28570

American (AMR) AF: 0.00488 AC: 217 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.0000406 AC: 1 AN: 24604

East Asian (EAS) AF: 0.00 AC: 0 AN: 38574

South Asian (SAS) AF: 0.0000737 AC: 6 AN: 81366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00492 AC: 26 AN: 5284

European-Non Finnish (NFE) AF: 0.000145 AC: 129 AN: 888880

Other (OTH) AF: 0.00772 AC: 403 AN: 52224

GnomAD4 genome AF: 0.0308 AC: 4674 AN: 151852 Hom.: 245 Cov.: 32 AF XY: 0.0302 AC XY: 2241 AN XY: 74206

African (AFR) AF: 0.107 AC: 4438 AN: 41368

American (AMR) AF: 0.0111 AC: 170 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67962

Other (OTH) AF: 0.0233 AC: 49 AN: 2106

Alfa AF: 0.0146 Hom.: 24

Bravo AF: 0.0355

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fanconi anemia complementation group D2 (1)
-	-	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	-0.82
CADD	Benign	1.9
DANN	Benign	0.59
PhyloP100		-0.62
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: rs34323624; hg19: chr3-10107215;