NM_001018115.3:c.310A>G

Variant names:

• chr3-10034731-A-G
• rs774299094
• NM_001018115.3:c.310A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001018115.3(FANCD2):​c.310A>G​(p.Ile104Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000352 in 1,420,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. I104T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.50
• Publications: 0 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14562964).
• BP6: Variant 3-10034731-A-G is Benign according to our data. Variant chr3-10034731-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407781.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.310A>G	p.Ile104Val	missense	Exon 5 of 44	NP_001018125.1
	FANCD2	NM_033084.6		c.310A>G	p.Ile104Val	missense	Exon 5 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.310A>G	p.Ile104Val	missense	Exon 5 of 42	NP_001361183.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.310A>G	p.Ile104Val	missense	Exon 5 of 44	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.310A>G	p.Ile104Val	missense	Exon 5 of 43	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.310A>G	p.Ile104Val	missense	Exon 5 of 44	ENSP00000398754.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000158 AC: 3 AN: 190066 AF XY: 0.0000198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1420280 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 702796

African (AFR) AF: 0.00 AC: 0 AN: 32694

American (AMR) AF: 0.00 AC: 0 AN: 37926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.0000524 AC: 2 AN: 38188

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4730

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090546

Other (OTH) AF: 0.00 AC: 0 AN: 58796

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000834 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)
-	1	-	Fanconi anemia complementation group D2 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Uncertain	0.049	D
Polyphen		0.054	B
Vest4		0.21
MutPred		0.25		Loss of catalytic residue at I104 (P = 0.0487)
MVP		0.56
MPC		0.15
ClinPred		0.071	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.12
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs774299094; hg19: chr3-10076415;