chr3-10065836-G-T

Variant names:

• chr3-10065836-G-T
• rs34608006
• NM_001018115.3:c.2270-28G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):​c.2270-28G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,417,858 control chromosomes in the GnomAD database, including 21,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3260 hom., cov: 32)
  • Exomes 𝑓: 0.17 (18497 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.04
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-10065836-G-T is Benign according to our data. Variant chr3-10065836-G-T is described in ClinVar as Benign. ClinVar VariationId is 257074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 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.2270-28G>T		intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.2270-28G>T		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.2270-28G>T		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.2270-28G>T		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.2270-28G>T		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.2270-28G>T		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29439 AN: 151974 Hom.: 3256 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.160 AC: 39693 AN: 247714 AF XY: 0.160

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0650

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.166 AC: 210428 AN: 1265766 Hom.: 18497 Cov.: 18 AF XY: 0.166 AC XY: 106263 AN XY: 639718

African (AFR) AF: 0.320 AC: 9472 AN: 29620

American (AMR) AF: 0.157 AC: 6957 AN: 44290

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 3891 AN: 24762

East Asian (EAS) AF: 0.0565 AC: 2188 AN: 38738

South Asian (SAS) AF: 0.184 AC: 15128 AN: 82290

European-Finnish (FIN) AF: 0.123 AC: 6547 AN: 53164

Middle Eastern (MID) AF: 0.162 AC: 869 AN: 5370

European-Non Finnish (NFE) AF: 0.168 AC: 156450 AN: 933702

Other (OTH) AF: 0.166 AC: 8926 AN: 53830

GnomAD4 genome AF: 0.194 AC: 29462 AN: 152092 Hom.: 3260 Cov.: 32 AF XY: 0.189 AC XY: 14024 AN XY: 74332

African (AFR) AF: 0.308 AC: 12759 AN: 41470

American (AMR) AF: 0.144 AC: 2197 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3472

East Asian (EAS) AF: 0.0640 AC: 331 AN: 5170

South Asian (SAS) AF: 0.165 AC: 794 AN: 4826

European-Finnish (FIN) AF: 0.116 AC: 1226 AN: 10578

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10993 AN: 67988

Other (OTH) AF: 0.170 AC: 358 AN: 2112

Alfa AF: 0.179 Hom.: 513

Bravo AF: 0.203

Asia WGS AF: 0.113 AC: 396 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.7
DANN	Benign	0.70
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs34608006; hg19: chr3-10107520;