rs35557429

Variant names:

• chr3-10049365-C-G
• rs35557429
• NM_001018115.3:c.1414-9C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-10049365-C-G
• chr3-10049365-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001018115.3(FANCD2):​c.1414-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,436 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Scores: Splicing: ADA: 0.1595
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0450
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1414-9C>G		intron_variant	Intron 16 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1414-9C>G		intron_variant	Intron 16 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384436 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 690210

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

African (AFR) AF: 0.00 AC: 0 AN: 30944

American (AMR) AF: 0.00 AC: 0 AN: 42926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 39220

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047922

Other (OTH) AF: 0.00 AC: 0 AN: 57562

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.21
DANN	Benign	0.56
PhyloP100		0.045

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.16		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: rs35557429; hg19: chr3-10091049;