rs375412395

Variant names:

• chr3-10049400-T-C
• rs375412395
• NM_001018115.3:c.1440T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001018115.3(FANCD2):​c.1440T>C​(p.His480His) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.796
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-10049400-T-C is Benign according to our data. Variant chr3-10049400-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241732.
• BP7: Synonymous conserved (PhyloP=-0.796 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.1440T>C	p.His480His	synonymous	Exon 17 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1440T>C	p.His480His	synonymous	Exon 17 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.1440T>C	p.His480His	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.1440T>C	p.His480His	synonymous	Exon 17 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1440T>C	p.His480His	synonymous	Exon 17 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1440T>C	p.His480His	synonymous	Exon 17 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 361 AN: 139806 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.00754

Gnomad AMR AF: 0.00279

Gnomad ASJ AF: 0.00247

Gnomad EAS AF: 0.000596

Gnomad SAS AF: 0.000892

Gnomad FIN AF: 0.00194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00264

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251014 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000169 AC: 244 AN: 1443088 Hom.: 0 Cov.: 34 AF XY: 0.000167 AC XY: 120 AN XY: 717800

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

African (AFR) AF: 0.000768 AC: 25 AN: 32538

American (AMR) AF: 0.000227 AC: 10 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.000157 AC: 4 AN: 25458

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39290

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86014

European-Finnish (FIN) AF: 0.000326 AC: 17 AN: 52096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.000141 AC: 155 AN: 1098898

Other (OTH) AF: 0.000457 AC: 27 AN: 59134

⚠️ 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: 0.00257 AC: 360 AN: 139930 Hom.: 0 Cov.: 32 AF XY: 0.00231 AC XY: 158 AN XY: 68372

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

African (AFR) AF: 0.00435 AC: 161 AN: 36978

American (AMR) AF: 0.00279 AC: 39 AN: 13980

Ashkenazi Jewish (ASJ) AF: 0.00247 AC: 8 AN: 3240

East Asian (EAS) AF: 0.000598 AC: 3 AN: 5018

South Asian (SAS) AF: 0.000892 AC: 4 AN: 4482

European-Finnish (FIN) AF: 0.00194 AC: 19 AN: 9778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00181 AC: 115 AN: 63468

Other (OTH) AF: 0.00261 AC: 5 AN: 1916

⚠️ 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: 0.00937 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.2
DANN	Benign	0.58
PhyloP100		-0.80
Mutation Taster		=99/1	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: rs375412395; hg19: chr3-10091084; COSMIC: COSV55032425; COSMIC: COSV55032425;