NM_001018115.3:c.1170C>T

Variant names:

• chr3-10046615-C-T
• rs112887807
• NM_001018115.3:c.1170C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001018115.3(FANCD2):​c.1170C>T​(p.Ser390Ser) 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: 47)
  • Exomes 𝑓: 0.36 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.913
• 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: 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-10046615-C-T is Benign according to our data. Variant chr3-10046615-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 342261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.913 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1170C>T	p.Ser390Ser	synonymous_variant	Exon 15 of 44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1170C>T	p.Ser390Ser	synonymous_variant	Exon 15 of 44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 62834 AN: 137238 Hom.: 0 Cov.: 47

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.457

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.223 AC: 34024 AN: 152508 AF XY: 0.224

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.0929

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.282

Gnomad OTH exome AF: 0.166

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.364 AC: 297604 AN: 816742 Hom.: 0 Cov.: 55 AF XY: 0.364 AC XY: 149044 AN XY: 409286

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

African (AFR) AF: 0.416 AC: 7846 AN: 18852

American (AMR) AF: 0.262 AC: 6817 AN: 26036

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 5694 AN: 15084

East Asian (EAS) AF: 0.305 AC: 8021 AN: 26268

South Asian (SAS) AF: 0.217 AC: 9018 AN: 41480

European-Finnish (FIN) AF: 0.442 AC: 17584 AN: 39822

Middle Eastern (MID) AF: 0.401 AC: 1514 AN: 3776

European-Non Finnish (NFE) AF: 0.373 AC: 227884 AN: 610350

Other (OTH) AF: 0.377 AC: 13226 AN: 35074

⚠️ 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: 0.458 AC: 62877 AN: 137334 Hom.: 0 Cov.: 47 AF XY: 0.456 AC XY: 30573 AN XY: 67034

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

African (AFR) AF: 0.478 AC: 18176 AN: 38060

American (AMR) AF: 0.418 AC: 5602 AN: 13388

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1406 AN: 3092

East Asian (EAS) AF: 0.407 AC: 1836 AN: 4508

South Asian (SAS) AF: 0.406 AC: 1704 AN: 4192

European-Finnish (FIN) AF: 0.461 AC: 4346 AN: 9422

Middle Eastern (MID) AF: 0.462 AC: 120 AN: 260

European-Non Finnish (NFE) AF: 0.461 AC: 28482 AN: 61722

Other (OTH) AF: 0.452 AC: 844 AN: 1868

⚠️ 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: 0.381 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:2

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fanconi anemia Benign:1

Aug 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.91
Mutation Taster		=100/0	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: rs112887807; hg19: chr3-10088299; COSMIC: COSV55040833; COSMIC: COSV55040833;