rs73126218

Variant names:

• chr3-10046659-A-G
• rs73126218
• NM_001018115.3:c.1214A>G
• FANCD2 p.Asn405Ser

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001018115.3(FANCD2):​c.1214A>G​(p.Asn405Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (0 hom., cov: 49)
  • Exomes 𝑓: 0.39 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.211
• Publications: 41 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024337769).
• BP6: Variant 3-10046659-A-G is Benign according to our data. Variant chr3-10046659-A-G is described in ClinVar as Benign. ClinVar VariationId is 342263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1214A>G	p.Asn405Ser	missense	Exon 15 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1214A>G	p.Asn405Ser	missense	Exon 15 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.1214A>G	p.Asn405Ser	missense	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.1214A>G	p.Asn405Ser	missense	Exon 15 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1214A>G	p.Asn405Ser	missense	Exon 15 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1214A>G	p.Asn405Ser	missense	Exon 15 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 65086 AN: 141890 Hom.: 0 Cov.: 49

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.460

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.452

GnomAD2 exomes AF: 0.228 AC: 37223 AN: 163454 AF XY: 0.229

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.174

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.389 AC: 373029 AN: 959700 Hom.: 0 Cov.: 62 AF XY: 0.387 AC XY: 184921 AN XY: 478068

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

African (AFR) AF: 0.430 AC: 9580 AN: 22274

American (AMR) AF: 0.279 AC: 7940 AN: 28424

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 6530 AN: 16934

East Asian (EAS) AF: 0.317 AC: 8945 AN: 28184

South Asian (SAS) AF: 0.254 AC: 12076 AN: 47514

European-Finnish (FIN) AF: 0.445 AC: 18769 AN: 42214

Middle Eastern (MID) AF: 0.414 AC: 1709 AN: 4128

European-Non Finnish (NFE) AF: 0.399 AC: 291615 AN: 730044

Other (OTH) AF: 0.397 AC: 15865 AN: 39984

⚠️ 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: 65132 AN: 141990 Hom.: 0 Cov.: 49 AF XY: 0.457 AC XY: 31673 AN XY: 69286

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

African (AFR) AF: 0.478 AC: 18658 AN: 39070

American (AMR) AF: 0.420 AC: 5852 AN: 13926

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1487 AN: 3252

East Asian (EAS) AF: 0.411 AC: 1939 AN: 4714

South Asian (SAS) AF: 0.410 AC: 1782 AN: 4346

European-Finnish (FIN) AF: 0.463 AC: 4531 AN: 9796

Middle Eastern (MID) AF: 0.464 AC: 130 AN: 280

European-Non Finnish (NFE) AF: 0.462 AC: 29491 AN: 63798

Other (OTH) AF: 0.453 AC: 879 AN: 1942

⚠️ 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: 0.243 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.88
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.21
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.032
Sift	Benign	0.31	T
Sift4G	Benign	0.81	T
Varity_R		0.032
gMVP		0.081
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs73126218;

hg19: chr3-10088343;

COSMIC: COSV55032016;

COSMIC: COSV55032016;