rs2237857

Variant names:

• chr9-35076758-G-A
• rs2237857
• NM_004629.2:c.890C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-35076758-G-A
• chr9-35076758-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004629.2(FANCG):​c.890C>T​(p.Thr297Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,128 control chromosomes in the GnomAD database, including 609 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. T297A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (439 hom.)
• Consequence: FANCG NM_004629.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:16 O:1
• Conservation: PhyloP100: 1.27
• Publications: 24 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=0.0016728342).
• BP6: Variant 9-35076758-G-A is Benign according to our data. Variant chr9-35076758-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0852 is higher than 0.05.

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.890C>T	p.Thr297Ile	missense	Exon 7 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.890C>T	p.Thr297Ile	missense	Exon 7 of 14	ENSP00000367910.4	O15287
	FANCG	ENST00000425676.5	TSL:1	n.*366C>T		non_coding_transcript_exon	Exon 6 of 13	ENSP00000412793.1	F8WC08
	FANCG	ENST00000425676.5	TSL:1	n.*366C>T		3_prime_UTR	Exon 6 of 13	ENSP00000412793.1	F8WC08

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4480 AN: 152116 Hom.: 171 Cov.: 32

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0154 AC: 3867 AN: 251494 AF XY: 0.0152

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0298

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.00859 AC: 12564 AN: 1461894 Hom.: 439 Cov.: 34 AF XY: 0.00927 AC XY: 6740 AN XY: 727248

African (AFR) AF: 0.0961 AC: 3216 AN: 33480

American (AMR) AF: 0.00539 AC: 241 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.0761 AC: 3020 AN: 39700

South Asian (SAS) AF: 0.0434 AC: 3740 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.00132 AC: 1471 AN: 1112012

Other (OTH) AF: 0.0132 AC: 798 AN: 60396

GnomAD4 genome AF: 0.0294 AC: 4481 AN: 152234 Hom.: 170 Cov.: 32 AF XY: 0.0302 AC XY: 2249 AN XY: 74444

African (AFR) AF: 0.0876 AC: 3636 AN: 41512

American (AMR) AF: 0.0120 AC: 184 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.0508 AC: 263 AN: 5174

South Asian (SAS) AF: 0.0495 AC: 239 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68028

Other (OTH) AF: 0.0223 AC: 47 AN: 2108

Alfa AF: 0.0121 Hom.: 198

Bravo AF: 0.0321

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0815 AC: 359

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.0177 AC: 2150

Asia WGS AF: 0.0590 AC: 203 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	4	Fanconi anemia complementation group G (5)
-	-	3	Fanconi anemia (3)
-	-	3	not provided (3)
-	-	3	not specified (4)
-	-	1	Amyotrophic Lateral Sclerosis, Dominant (1)
-	-	1	FANCG-related disorder (1)
-	-	1	Inclusion Body Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.043
Sift	Benign	0.057	T
Sift4G	Uncertain	0.041	D
Polyphen		0.28	B
Vest4		0.056
MPC		0.35
ClinPred		0.0082	T
GERP RS		4.5
Varity_R		0.035
gMVP		0.095
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2237857; hg19: chr9-35076755; COSMIC: COSV62719936; COSMIC: COSV62719936;