3-10046601-T-G

Variant names:

• chr3-10046601-T-G
• rs149125003
• NM_001018115.3:c.1156T>G

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.1156T>G​(p.Phe386Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 151,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 47)
  • Exomes 𝑓: 0.00059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0210
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008343905).
• BP6: Variant 3-10046601-T-G is Benign according to our data. Variant chr3-10046601-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241729.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.1156T>G	p.Phe386Val	missense	Exon 15 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1156T>G	p.Phe386Val	missense	Exon 15 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.1156T>G	p.Phe386Val	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.1156T>G	p.Phe386Val	missense	Exon 15 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1156T>G	p.Phe386Val	missense	Exon 15 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1156T>G	p.Phe386Val	missense	Exon 15 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 710 AN: 150960 Hom.: 0 Cov.: 47

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00466

Gnomad EAS AF: 0.00330

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00522

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00532

GnomAD2 exomes AF: 0.0000440 AC: 11 AN: 250164 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000591 AC: 858 AN: 1450622 Hom.: 0 Cov.: 47 AF XY: 0.000622 AC XY: 449 AN XY: 721876

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

African (AFR) AF: 0.000209 AC: 7 AN: 33444

American (AMR) AF: 0.00581 AC: 247 AN: 42494

Ashkenazi Jewish (ASJ) AF: 0.000848 AC: 22 AN: 25956

East Asian (EAS) AF: 0.00132 AC: 52 AN: 39344

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86112

European-Finnish (FIN) AF: 0.00159 AC: 84 AN: 52808

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000340 AC: 376 AN: 1104752

Other (OTH) AF: 0.00103 AC: 62 AN: 59948

⚠️ 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: 0.00473 AC: 715 AN: 151072 Hom.: 0 Cov.: 47 AF XY: 0.00489 AC XY: 361 AN XY: 73882

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

African (AFR) AF: 0.000915 AC: 38 AN: 41514

American (AMR) AF: 0.0202 AC: 298 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.00466 AC: 16 AN: 3436

East Asian (EAS) AF: 0.00331 AC: 17 AN: 5132

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00522 AC: 55 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00395 AC: 267 AN: 67568

Other (OTH) AF: 0.00527 AC: 11 AN: 2088

⚠️ 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: 0.00351 Hom.: 0

ExAC AF: 0.00335 AC: 407

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia (2)
-	-	1	not specified (1)
-	-	1	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.021
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.048
Sift	Benign	0.038	D
Sift4G	Uncertain	0.056	T
Polyphen		0.16	B
Vest4		0.45
MVP		0.31
MPC		0.22
ClinPred		0.028	T
GERP RS		-1.8
Varity_R		0.26
gMVP		0.25
Mutation Taster		=77/23	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: rs149125003; hg19: chr3-10088285; COSMIC: COSV99811121;