rs10222446

Variant names:

• chr3-10049351-T-C
• rs10222446
• NM_001018115.3:c.1414-23T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-10049351-T-C
• chr3-10049351-T-G

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.1414-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,117,110 control chromosomes in the GnomAD database, including 48,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (13140 hom., cov: 30)
  • Exomes 𝑓: 0.28 (35531 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.483
• Publications: 9 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=-0.91).
• BP6: Variant 3-10049351-T-C is Benign according to our data. Variant chr3-10049351-T-C is described in ClinVar as Benign. ClinVar VariationId is 257068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 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.1414-23T>C		intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1414-23T>C		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.1414-23T>C		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.1414-23T>C		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1414-23T>C		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1414-23T>C		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.469 AC: 55328 AN: 118078 Hom.: 13119 Cov.: 30

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.414

GnomAD2 exomes AF: 0.206 AC: 39456 AN: 191370 AF XY: 0.191

Gnomad AFR exome AF: 0.759

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.0914

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.279 AC: 278499 AN: 998934 Hom.: 35531 Cov.: 33 AF XY: 0.278 AC XY: 138905 AN XY: 499934

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

African (AFR) AF: 0.779 AC: 21386 AN: 27460

American (AMR) AF: 0.232 AC: 7914 AN: 34166

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 6987 AN: 19682

East Asian (EAS) AF: 0.132 AC: 3925 AN: 29676

South Asian (SAS) AF: 0.222 AC: 14683 AN: 66174

European-Finnish (FIN) AF: 0.250 AC: 9549 AN: 38134

Middle Eastern (MID) AF: 0.314 AC: 1326 AN: 4224

European-Non Finnish (NFE) AF: 0.271 AC: 199603 AN: 736590

Other (OTH) AF: 0.306 AC: 13126 AN: 42828

⚠️ 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 AF: 0.469 AC: 55390 AN: 118176 Hom.: 13140 Cov.: 30 AF XY: 0.456 AC XY: 26216 AN XY: 57496

African (AFR) AF: 0.774 AC: 28570 AN: 36906

American (AMR) AF: 0.327 AC: 3804 AN: 11628

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1030 AN: 2666

East Asian (EAS) AF: 0.186 AC: 683 AN: 3666

South Asian (SAS) AF: 0.260 AC: 930 AN: 3572

European-Finnish (FIN) AF: 0.283 AC: 2094 AN: 7390

Middle Eastern (MID) AF: 0.373 AC: 82 AN: 220

European-Non Finnish (NFE) AF: 0.347 AC: 17283 AN: 49820

Other (OTH) AF: 0.412 AC: 662 AN: 1606

Alfa AF: 0.357 Hom.: 1361

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.91
CADD	Benign	0.41
DANN	Benign	0.67
PhyloP100		-0.48
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs10222446; hg19: chr3-10091035; COSMIC: COSV55032714; COSMIC: COSV55032714;