rs6785756

Variant names:

• chr3-10049469-C-T
• rs6785756
• NM_001018115.3:c.1509C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001018115.3(FANCD2):​c.1509C>T​(p.Asn503Asn) variant causes a synonymous 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1068 hom., cov: 32)
  • Exomes 𝑓: 0.045 (3032 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.872
• Publications: 7 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-10049469-C-T is Benign according to our data. Variant chr3-10049469-C-T is described in ClinVar as Benign. ClinVar VariationId is 257070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.872 with no splicing effect.

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.1509C>T	p.Asn503Asn	synonymous	Exon 17 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1509C>T	p.Asn503Asn	synonymous	Exon 17 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.1509C>T	p.Asn503Asn	synonymous	Exon 17 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.1509C>T	p.Asn503Asn	synonymous	Exon 17 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1509C>T	p.Asn503Asn	synonymous	Exon 17 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1509C>T	p.Asn503Asn	synonymous	Exon 17 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.159 AC: 21029 AN: 132134 Hom.: 1066 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.145

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.0300 AC: 7152 AN: 238040 AF XY: 0.0284

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0372

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0452 AC: 57650 AN: 1275376 Hom.: 3032 Cov.: 34 AF XY: 0.0473 AC XY: 30103 AN XY: 636740

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

African (AFR) AF: 0.130 AC: 3390 AN: 26166

American (AMR) AF: 0.0566 AC: 2304 AN: 40686

Ashkenazi Jewish (ASJ) AF: 0.0641 AC: 1492 AN: 23278

East Asian (EAS) AF: 0.0282 AC: 1070 AN: 37906

South Asian (SAS) AF: 0.0929 AC: 7271 AN: 78306

European-Finnish (FIN) AF: 0.0455 AC: 2210 AN: 48540

Middle Eastern (MID) AF: 0.0491 AC: 247 AN: 5032

European-Non Finnish (NFE) AF: 0.0380 AC: 36549 AN: 962962

Other (OTH) AF: 0.0594 AC: 3117 AN: 52500

⚠️ 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: 0.159 AC: 21047 AN: 132256 Hom.: 1068 Cov.: 32 AF XY: 0.153 AC XY: 9907 AN XY: 64558

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

African (AFR) AF: 0.261 AC: 9045 AN: 34630

American (AMR) AF: 0.117 AC: 1597 AN: 13596

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 384 AN: 3034

East Asian (EAS) AF: 0.0519 AC: 252 AN: 4856

South Asian (SAS) AF: 0.144 AC: 595 AN: 4146

European-Finnish (FIN) AF: 0.0896 AC: 830 AN: 9266

Middle Eastern (MID) AF: 0.140 AC: 36 AN: 258

European-Non Finnish (NFE) AF: 0.132 AC: 7904 AN: 59864

Other (OTH) AF: 0.135 AC: 251 AN: 1856

⚠️ 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: 0.127 Hom.: 171

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group D2 (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.1
DANN	Benign	0.57
PhyloP100		0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs6785756; hg19: chr3-10091153; COSMIC: COSV55032395; COSMIC: COSV55032395;