chr3-10064848-C-T

Variant names:

• chr3-10064848-C-T
• rs3864017
• NM_001018115.3:c.2141C>T

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.2141C>T​(p.Pro714Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,536,518 control chromosomes in the GnomAD database, including 14,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P714Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (1870 hom., cov: 32)
  • Exomes 𝑓: 0.14 (12378 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.0900
• Publications: 37 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 (MetaRNN=0.0033615232).
• BP6: Variant 3-10064848-C-T is Benign according to our data. Variant chr3-10064848-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 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.2141C>T	p.Pro714Leu	missense	Exon 23 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.2141C>T	p.Pro714Leu	missense	Exon 23 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.2141C>T	p.Pro714Leu	missense	Exon 23 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.2141C>T	p.Pro714Leu	missense	Exon 23 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.2141C>T	p.Pro714Leu	missense	Exon 23 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.2141C>T	p.Pro714Leu	missense	Exon 23 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.188 AC: 27645 AN: 147016 Hom.: 1866 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0626

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.132

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.142 AC: 34399 AN: 242424 AF XY: 0.142

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0524

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.145 AC: 201031 AN: 1389386 Hom.: 12378 Cov.: 35 AF XY: 0.145 AC XY: 100652 AN XY: 692730

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

African (AFR) AF: 0.270 AC: 8312 AN: 30780

American (AMR) AF: 0.146 AC: 6388 AN: 43654

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 3776 AN: 25428

East Asian (EAS) AF: 0.0514 AC: 2020 AN: 39312

South Asian (SAS) AF: 0.165 AC: 13856 AN: 84036

European-Finnish (FIN) AF: 0.121 AC: 6318 AN: 52124

Middle Eastern (MID) AF: 0.147 AC: 805 AN: 5458

European-Non Finnish (NFE) AF: 0.144 AC: 151073 AN: 1050814

Other (OTH) AF: 0.147 AC: 8483 AN: 57780

⚠️ 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: 0.188 AC: 27669 AN: 147132 Hom.: 1870 Cov.: 32 AF XY: 0.184 AC XY: 13178 AN XY: 71752

African (AFR) AF: 0.284 AC: 11504 AN: 40552

American (AMR) AF: 0.143 AC: 2103 AN: 14734

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 509 AN: 3344

East Asian (EAS) AF: 0.0625 AC: 323 AN: 5166

South Asian (SAS) AF: 0.162 AC: 751 AN: 4650

European-Finnish (FIN) AF: 0.122 AC: 1202 AN: 9854

Middle Eastern (MID) AF: 0.125 AC: 35 AN: 280

European-Non Finnish (NFE) AF: 0.162 AC: 10666 AN: 65650

Other (OTH) AF: 0.168 AC: 340 AN: 2022

Alfa AF: 0.165 Hom.: 509

ExAC AF: 0.154 AC: 18760

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group D2 (4)
-	-	3	not specified (4)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)
-	-	1	Fanconi anemia complementation group A (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.1
DANN	Benign	0.46
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.090
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.028
Sift	Benign	0.25	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.052
MPC		0.15
ClinPred		0.0018	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.15
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: rs3864017; hg19: chr3-10106532; COSMIC: COSV55033303;