3-10063977-CTT-CT

Variant names:

• chr3-10063977-CT-C
• rs797045572
• NM_001018115.3:c.1947+69delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_033084.6(FANCD2):​c.1947+69delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.023 (14 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_033084.6 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.373
• 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033084.6. 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.1947+69delT		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.1947+69delT		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.1947+69delT		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.1947+67delT		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.1947+67delT		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.1947+67delT		intron	N/A	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 183 AN: 139940 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000214

Gnomad ASJ AF: 0.000307

Gnomad EAS AF: 0.000414

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.000308

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000860

Gnomad OTH AF: 0.00159

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0226 AC: 28994 AN: 1280124 Hom.: 14 AF XY: 0.0254 AC XY: 16116 AN XY: 634840

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

African (AFR) AF: 0.0168 AC: 503 AN: 30002

American (AMR) AF: 0.0113 AC: 465 AN: 41230

Ashkenazi Jewish (ASJ) AF: 0.00907 AC: 218 AN: 24034

East Asian (EAS) AF: 0.0122 AC: 435 AN: 35640

South Asian (SAS) AF: 0.0246 AC: 1912 AN: 77638

European-Finnish (FIN) AF: 0.0361 AC: 1440 AN: 39936

Middle Eastern (MID) AF: 0.0455 AC: 192 AN: 4218

European-Non Finnish (NFE) AF: 0.0234 AC: 22794 AN: 973572

Other (OTH) AF: 0.0192 AC: 1035 AN: 53854

⚠️ 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: 0.00129 AC: 181 AN: 140058 Hom.: 1 Cov.: 32 AF XY: 0.00174 AC XY: 118 AN XY: 67958

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

African (AFR) AF: 0.000578 AC: 22 AN: 38050

American (AMR) AF: 0.000214 AC: 3 AN: 14044

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 1 AN: 3258

East Asian (EAS) AF: 0.000415 AC: 2 AN: 4820

South Asian (SAS) AF: 0.0212 AC: 92 AN: 4332

European-Finnish (FIN) AF: 0.000308 AC: 3 AN: 9730

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.000860 AC: 54 AN: 62782

Other (OTH) AF: 0.00157 AC: 3 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: 0.00274 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37
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: rs797045572; hg19: chr3-10105661;