rs34936017

chr3-10039727-A-G

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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:5 O:1
• Conservation: PhyloP100: 2.45

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.577A>G	p.Thr193Ala	missense_variant	9/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.577A>G	p.Thr193Ala	missense_variant	9/44		NM_001018115.3	P2

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

GnomAD3 exomes AF: 0.00597 AC: 1501 AN: 251396 Hom.: 38 AF XY: 0.00741 AC XY: 1007 AN XY: 135868

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 SAS exome AF: 0.0365

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

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00952

Gnomad4 SAS exome AF: 0.0356

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000238

Gnomad4 OTH exome AF: 0.00401

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

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0156

Gnomad4 SAS AF: 0.0421

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000871 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

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 03, 2021	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 23, 2015

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.70	T;T;.;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	0.91	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.93	N;N;N;D
REVEL	Benign	0.13
Sift	Benign	0.49	T;T;T;T
Sift4G	Benign	0.35	T;T;T;D
Polyphen		0.23, 1.0	.;B;B;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs34936017; hg19: chr3-10081411; COSMIC: COSV104599168; COSMIC: COSV104599168;