rs45510294

Variant names:

• chr3-10032845-A-C
• rs45510294
• NM_001018115.3:c.78A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001018115.3(FANCD2):​c.78A>C​(p.Gln26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,120 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q26P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: -0.128
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016909897).
• BP6: Variant 3-10032845-A-C is Benign according to our data. Variant chr3-10032845-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456361.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.78A>C	p.Gln26His	missense	Exon 3 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.78A>C	p.Gln26His	missense	Exon 3 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.78A>C	p.Gln26His	missense	Exon 3 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.78A>C	p.Gln26His	missense	Exon 3 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.78A>C	p.Gln26His	missense	Exon 3 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.78A>C	p.Gln26His	missense	Exon 3 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000766 AC: 192 AN: 250632 AF XY: 0.000826

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.00108 AC: 1577 AN: 1460818 Hom.: 3 Cov.: 30 AF XY: 0.00106 AC XY: 771 AN XY: 726676

African (AFR) AF: 0.000149 AC: 5 AN: 33458

American (AMR) AF: 0.000179 AC: 8 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.000302 AC: 26 AN: 85980

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53412

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00126 AC: 1403 AN: 1111394

Other (OTH) AF: 0.000961 AC: 58 AN: 60372

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74476

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000672

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.000927

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	2	1	Fanconi anemia complementation group D2 (3)
-	-	2	Fanconi anemia (2)
-	-	1	FANCD2-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.9
DANN	Benign	0.92
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.13
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.069
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.80	P
Vest4		0.17
MutPred		0.15		Gain of catalytic residue at L28 (P = 0.0522)
MVP		0.48
MPC		0.38
ClinPred		0.0082	T
GERP RS		-1.7
Varity_R		0.037
gMVP		0.23
Mutation Taster		=96/4	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: rs45510294; hg19: chr3-10074529; COSMIC: COSV55036019;