rs56350437

Variant names:

• chr3-10043722-G-T
• rs56350437
• NM_001018115.3:c.1099-107G>T

Variant summary

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

The NM_001018115.3(FANCD2):​c.1099-107G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.628
• Publications: 1 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=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1099-107G>T		intron_variant	Intron 13 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1099-107G>T		intron_variant	Intron 13 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 792 AN: 130220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00865

Gnomad AMR AF: 0.00734

Gnomad ASJ AF: 0.00164

Gnomad EAS AF: 0.00260

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00493

Gnomad MID AF: 0.00368

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.00437

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00757 AC: 7359 AN: 972122 Hom.: 1 Cov.: 15 AF XY: 0.00809 AC XY: 3996 AN XY: 493720

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

African (AFR) AF: 0.00869 AC: 221 AN: 25422

American (AMR) AF: 0.00835 AC: 290 AN: 34730

Ashkenazi Jewish (ASJ) AF: 0.00649 AC: 135 AN: 20794

East Asian (EAS) AF: 0.00501 AC: 163 AN: 32524

South Asian (SAS) AF: 0.0120 AC: 772 AN: 64530

European-Finnish (FIN) AF: 0.00332 AC: 154 AN: 46366

Middle Eastern (MID) AF: 0.0122 AC: 53 AN: 4354

European-Non Finnish (NFE) AF: 0.00756 AC: 5299 AN: 700516

Other (OTH) AF: 0.00634 AC: 272 AN: 42886

⚠️ 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: AS_VQSR AF: 0.00610 AC: 795 AN: 130334 Hom.: 0 Cov.: 33 AF XY: 0.00619 AC XY: 396 AN XY: 63974

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

African (AFR) AF: 0.0101 AC: 363 AN: 35988

American (AMR) AF: 0.00733 AC: 95 AN: 12962

Ashkenazi Jewish (ASJ) AF: 0.00164 AC: 5 AN: 3052

East Asian (EAS) AF: 0.00261 AC: 12 AN: 4604

South Asian (SAS) AF: 0.0111 AC: 43 AN: 3888

European-Finnish (FIN) AF: 0.00493 AC: 46 AN: 9332

Middle Eastern (MID) AF: 0.00394 AC: 1 AN: 254

European-Non Finnish (NFE) AF: 0.00374 AC: 216 AN: 57706

Other (OTH) AF: 0.00431 AC: 8 AN: 1854

⚠️ 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: 0.0141 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.70
PhyloP100		-0.63
Mutation Taster		=39/61	disease causing

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: rs56350437; hg19: chr3-10085406;