3-10048089-A-G

Variant names:

• chr3-10048089-A-G
• rs7615646
• NM_001018115.3:c.1413+38A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001018115.3(FANCD2):​c.1413+38A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (0 hom., cov: 47)
  • Exomes 𝑓: 0.33 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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>G		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.1413+38A>G		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.1413+38A>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.1413+38A>G		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.1413+38A>G		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.1413+38A>G		intron	N/A	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 60252 AN: 140926 Hom.: 0 Cov.: 47

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.413

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.423

GnomAD2 exomes AF: 0.179 AC: 25980 AN: 145128 AF XY: 0.172

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.172

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.330 AC: 367961 AN: 1114936 Hom.: 0 Cov.: 44 AF XY: 0.335 AC XY: 187661 AN XY: 560656

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.362 AC: 10264 AN: 28378

American (AMR) AF: 0.348 AC: 13705 AN: 39370

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 8588 AN: 22186

East Asian (EAS) AF: 0.358 AC: 12696 AN: 35460

South Asian (SAS) AF: 0.321 AC: 22509 AN: 70214

European-Finnish (FIN) AF: 0.441 AC: 21453 AN: 48592

Middle Eastern (MID) AF: 0.378 AC: 1828 AN: 4836

European-Non Finnish (NFE) AF: 0.318 AC: 259741 AN: 817508

Other (OTH) AF: 0.355 AC: 17177 AN: 48392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.428 AC: 60300 AN: 141044 Hom.: 0 Cov.: 47 AF XY: 0.427 AC XY: 29443 AN XY: 68896

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.441 AC: 17448 AN: 39578

American (AMR) AF: 0.388 AC: 5344 AN: 13760

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1347 AN: 3216

East Asian (EAS) AF: 0.385 AC: 1715 AN: 4454

South Asian (SAS) AF: 0.364 AC: 1554 AN: 4272

European-Finnish (FIN) AF: 0.441 AC: 4270 AN: 9680

Middle Eastern (MID) AF: 0.414 AC: 96 AN: 232

European-Non Finnish (NFE) AF: 0.434 AC: 27378 AN: 63090

Other (OTH) AF: 0.423 AC: 807 AN: 1908

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0610 Hom.: 994

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.4
DANN	Benign	0.46
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism

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: rs7615646; hg19: chr3-10089773; COSMIC: COSV55031871; COSMIC: COSV55031871;