3-10035158-CTTT-CT

Variant names:

• chr3-10035158-CTT-C
• rs55973240
• NM_001018115.3:c.378-6_378-5delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):​c.378-6_378-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,433,924 control chromosomes in the GnomAD database, including 27,271 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4999 hom., cov: 25)
  • Exomes 𝑓: 0.19 (22272 hom.)
• Consequence: FANCD2 NM_001018115.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.334
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 3-10035158-CTT-C is Benign according to our data. Variant chr3-10035158-CTT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 342255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.378-6_378-5delTT		splice_region intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.378-6_378-5delTT		splice_region intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.378-6_378-5delTT		splice_region intron	N/A	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.378-14_378-13delTT		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.378-14_378-13delTT		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.378-14_378-13delTT		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34235 AN: 149558 Hom.: 4993 Cov.: 25

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0663

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.144

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.197

GnomAD2 exomes AF: 0.233 AC: 42195 AN: 181326 AF XY: 0.230

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.0966

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.190 AC: 243884 AN: 1284262 Hom.: 22272 AF XY: 0.189 AC XY: 121061 AN XY: 639418

African (AFR) AF: 0.455 AC: 14309 AN: 31436

American (AMR) AF: 0.182 AC: 7244 AN: 39796

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4075 AN: 22646

East Asian (EAS) AF: 0.0677 AC: 2252 AN: 33286

South Asian (SAS) AF: 0.202 AC: 15425 AN: 76232

European-Finnish (FIN) AF: 0.142 AC: 6434 AN: 45404

Middle Eastern (MID) AF: 0.185 AC: 971 AN: 5244

European-Non Finnish (NFE) AF: 0.187 AC: 182770 AN: 977580

Other (OTH) AF: 0.198 AC: 10404 AN: 52638

GnomAD4 genome AF: 0.229 AC: 34271 AN: 149662 Hom.: 4999 Cov.: 25 AF XY: 0.223 AC XY: 16321 AN XY: 73102

African (AFR) AF: 0.422 AC: 17325 AN: 41012

American (AMR) AF: 0.158 AC: 2366 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 522 AN: 3424

East Asian (EAS) AF: 0.0663 AC: 339 AN: 5116

South Asian (SAS) AF: 0.166 AC: 781 AN: 4710

European-Finnish (FIN) AF: 0.123 AC: 1228 AN: 10000

Middle Eastern (MID) AF: 0.131 AC: 38 AN: 290

European-Non Finnish (NFE) AF: 0.164 AC: 11019 AN: 67164

Other (OTH) AF: 0.197 AC: 408 AN: 2070

Alfa AF: 0.112 Hom.: 220

Bravo AF: 0.240

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group D2 (3)
-	-	2	Fanconi anemia (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs55973240; hg19: chr3-10076842;