rs72492998

Variant names:

• chr3-10046624-T-C
• rs72492998
• NM_001018115.3:c.1179T>C
• FANCD2 p.Thr393Thr

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001018115.3(FANCD2):​c.1179T>C​(p.Thr393Thr) 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (0 hom., cov: 48)
  • Exomes 𝑓: 0.38 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.281
• Publications: 15 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-10046624-T-C is Benign according to our data. Variant chr3-10046624-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 342262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.281 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.1179T>C	p.Thr393Thr	synonymous	Exon 15 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1179T>C	p.Thr393Thr	synonymous	Exon 15 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.1179T>C	p.Thr393Thr	synonymous	Exon 15 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.1179T>C	p.Thr393Thr	synonymous	Exon 15 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1179T>C	p.Thr393Thr	synonymous	Exon 15 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1179T>C	p.Thr393Thr	synonymous	Exon 15 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 63815 AN: 139174 Hom.: 0 Cov.: 48

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.458

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.236 AC: 35999 AN: 152394 AF XY: 0.237

Gnomad AFR exome AF: 0.280

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.180

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.384 AC: 335453 AN: 872610 Hom.: 0 Cov.: 59 AF XY: 0.384 AC XY: 167682 AN XY: 436850

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

African (AFR) AF: 0.432 AC: 8802 AN: 20364

American (AMR) AF: 0.287 AC: 7740 AN: 27010

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 6276 AN: 15970

East Asian (EAS) AF: 0.315 AC: 8516 AN: 27052

South Asian (SAS) AF: 0.254 AC: 11095 AN: 43744

European-Finnish (FIN) AF: 0.447 AC: 18407 AN: 41178

Middle Eastern (MID) AF: 0.413 AC: 1627 AN: 3942

European-Non Finnish (NFE) AF: 0.394 AC: 258364 AN: 656206

Other (OTH) AF: 0.394 AC: 14626 AN: 37144

⚠️ 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: InbreedingCoeff AF: 0.459 AC: 63860 AN: 139274 Hom.: 0 Cov.: 48 AF XY: 0.457 AC XY: 31050 AN XY: 67974

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

African (AFR) AF: 0.478 AC: 18371 AN: 38434

American (AMR) AF: 0.420 AC: 5706 AN: 13594

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1438 AN: 3154

East Asian (EAS) AF: 0.409 AC: 1871 AN: 4580

South Asian (SAS) AF: 0.409 AC: 1749 AN: 4278

European-Finnish (FIN) AF: 0.462 AC: 4418 AN: 9566

Middle Eastern (MID) AF: 0.462 AC: 123 AN: 266

European-Non Finnish (NFE) AF: 0.462 AC: 28953 AN: 62656

Other (OTH) AF: 0.452 AC: 861 AN: 1906

⚠️ 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: 0.387 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.9
DANN	Benign	0.69
PhyloP100		-0.28
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72492998;

hg19: chr3-10088308;

COSMIC: COSV55032659;

COSMIC: COSV55032659;