rs35984312

chr9-35079505-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004629.2(FANCG):c.20C>T(p.Ser7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,128 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S7S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (34 hom.)
• Consequence: FANCG NM_004629.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: -0.0400

Genes affected

FANCG (HGNC:3588): (FA complementation group G) 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 G. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034295917).
• BP6: Variant 9-35079505-G-A is Benign according to our data. Variant chr9-35079505-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134358.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=2, not_provided=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00172 (262/152332) while in subpopulation SAS AF= 0.00995 (48/4824). AF 95% confidence interval is 0.00771. There are 3 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCG	NM_004629.2	c.20C>T	p.Ser7Phe	missense_variant	1/14	ENST00000378643.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCG	ENST00000378643.8	c.20C>T	p.Ser7Phe	missense_variant	1/14	1	NM_004629.2	P2

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 152214 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00339 AC: 847 AN: 249940 Hom.: 9 AF XY: 0.00362 AC XY: 490 AN XY: 135248

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.0381

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00725

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00192 AC: 2801 AN: 1461796 Hom.: 34 Cov.: 31 AF XY: 0.00213 AC XY: 1551 AN XY: 727194

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.0374

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00716

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000698

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152332 Hom.: 3 Cov.: 31 AF XY: 0.00196 AC XY: 146 AN XY: 74488

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00326 Hom.: 6

Bravo AF: 0.00162

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00297 AC: 360

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group G Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 27, 2018	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

FANCG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	14
Dann	Benign	0.82
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.062
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.12	B;.
Vest4		0.18
MVP		0.82
MPC		0.24
ClinPred		0.0053	T
GERP RS		2.0
Varity_R		0.028
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35984312; hg19: chr9-35079502; COSMIC: COSV66213722; COSMIC: COSV66213722;