rs34936017

Variant names:

• chr3-10039727-A-G
• rs34936017
• NM_001018115.3:c.577A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018115.3(FANCD2):​c.577A>G​(p.Thr193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,062 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (97 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 2.45
• Publications: 13 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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=0.003047973).
• BP6: Variant 3-10039727-A-G is Benign according to our data. Variant chr3-10039727-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00214 (325/152204) while in subpopulation SAS AF = 0.0421 (203/4818). AF 95% confidence interval is 0.0374. There are 9 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.577A>G	p.Thr193Ala	missense	Exon 9 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.577A>G	p.Thr193Ala	missense	Exon 9 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.577A>G	p.Thr193Ala	missense	Exon 9 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.577A>G	p.Thr193Ala	missense	Exon 9 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.577A>G	p.Thr193Ala	missense	Exon 9 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.577A>G	p.Thr193Ala	missense	Exon 9 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 326 AN: 152086 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00597 AC: 1501 AN: 251396 AF XY: 0.00741

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0165

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00274 AC: 4012 AN: 1461858 Hom.: 97 Cov.: 31 AF XY: 0.00369 AC XY: 2683 AN XY: 727232

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00952 AC: 378 AN: 39698

South Asian (SAS) AF: 0.0356 AC: 3067 AN: 86248

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53414

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5762

European-Non Finnish (NFE) AF: 0.000238 AC: 265 AN: 1112004

Other (OTH) AF: 0.00401 AC: 242 AN: 60394

GnomAD4 genome AF: 0.00214 AC: 325 AN: 152204 Hom.: 9 Cov.: 31 AF XY: 0.00294 AC XY: 219 AN XY: 74412

African (AFR) AF: 0.000313 AC: 13 AN: 41542

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0156 AC: 81 AN: 5178

South Asian (SAS) AF: 0.0421 AC: 203 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000883 Hom.: 1

Bravo AF: 0.00117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00633 AC: 769

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group D2 (3)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.13
Sift	Benign	0.49	T
Sift4G	Benign	0.35	T
Polyphen		0.23	B
Vest4		0.21
MVP		0.67
MPC		0.15
ClinPred		0.018	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.12
gMVP		0.17
Mutation Taster		=95/5	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: rs34936017; hg19: chr3-10081411; COSMIC: COSV104599168; COSMIC: COSV104599168;