chr9-35079448-T-C

Variant names:

• chr9-35079448-T-C
• rs200677800
• NM_004629.2:c.77A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004629.2(FANCG):​c.77A>G​(p.Gln26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,120 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q26E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: FANCG NM_004629.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.707
• Publications: 5 publications found

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]

FANCG Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group G

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054132342).
• BP6: Variant 9-35079448-T-C is Benign according to our data. Variant chr9-35079448-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000545 (83/152322) while in subpopulation SAS AF = 0.0159 (77/4830). AF 95% confidence interval is 0.0131. There are 1 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004629.2. 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
	FANCG	NM_004629.2	MANE Select	c.77A>G	p.Gln26Arg	missense	Exon 1 of 14	NP_004620.1	O15287

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	ENST00000378643.8	TSL:1 MANE Select	c.77A>G	p.Gln26Arg	missense	Exon 1 of 14	ENSP00000367910.4	O15287
	FANCG	ENST00000425676.5	TSL:1	n.77A>G		non_coding_transcript_exon	Exon 1 of 13	ENSP00000412793.1	F8WC08
	FANCG	ENST00000448890.2	TSL:3	c.77A>G	p.Gln26Arg	missense	Exon 2 of 15	ENSP00000409607.2	O15287

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152204 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00233 AC: 582 AN: 249380 AF XY: 0.00310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000806

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00114 AC: 1670 AN: 1461798 Hom.: 32 Cov.: 31 AF XY: 0.00166 AC XY: 1205 AN XY: 727208

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0177 AC: 1525 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53330

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000620 AC: 69 AN: 1112008

Other (OTH) AF: 0.00116 AC: 70 AN: 60396

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152322 Hom.: 1 Cov.: 31 AF XY: 0.000792 AC XY: 59 AN XY: 74498

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0159 AC: 77 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group G (3)
-	-	1	FANCG-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0054	T
MetaSVM	Uncertain	0.043	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.71
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Benign	0.18	T
Sift4G	Benign	0.28	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.20		Gain of solvent accessibility (P = 0.1505)
MVP		0.84
MPC		0.24
ClinPred		0.067	T
GERP RS		5.0
PromoterAI		-0.083	Neutral
Varity_R		0.13
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200677800; hg19: chr9-35079445;