9-35075742-G-C

Variant names:

• chr9-35075742-G-C
• rs375757497
• NM_004629.2:c.1156C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004629.2(FANCG):​c.1156C>G​(p.Pro386Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P386R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000032 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCG NM_004629.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.799
• Publications: 2 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02786386).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	NM_004629.2	MANE Select	c.1156C>G	p.Pro386Ala	missense	Exon 10 of 14	NP_004620.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	ENST00000378643.8	TSL:1 MANE Select	c.1156C>G	p.Pro386Ala	missense	Exon 10 of 14	ENSP00000367910.4
	FANCG	ENST00000425676.5	TSL:1	n.*632C>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000412793.1
	FANCG	ENST00000425676.5	TSL:1	n.*632C>G		3_prime_UTR	Exon 9 of 13	ENSP00000412793.1

Frequencies

GnomAD3 genomes AF: 0.0000474 AC: 6 AN: 126538 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000883

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000861

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000616

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 24 AN: 232908 AF XY: 0.0000392

Gnomad AFR exome AF: 0.0000692

Gnomad AMR exome AF: 0.000612

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000711 AC: 32 AN: 450130 Hom.: 0 Cov.: 0 AF XY: 0.0000533 AC XY: 13 AN XY: 244034

African (AFR) AF: 0.000570 AC: 7 AN: 12276

American (AMR) AF: 0.000418 AC: 15 AN: 35902

Ashkenazi Jewish (ASJ) AF: 0.0000742 AC: 1 AN: 13482

East Asian (EAS) AF: 0.00 AC: 0 AN: 17300

South Asian (SAS) AF: 0.00 AC: 0 AN: 67228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3102

European-Non Finnish (NFE) AF: 0.0000241 AC: 6 AN: 249150

Other (OTH) AF: 0.000147 AC: 3 AN: 20358

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000316 AC: 4 AN: 126622 Hom.: 0 Cov.: 29 AF XY: 0.0000167 AC XY: 1 AN XY: 59744

African (AFR) AF: 0.0000881 AC: 3 AN: 34056

American (AMR) AF: 0.0000859 AC: 1 AN: 11638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3198

East Asian (EAS) AF: 0.00 AC: 0 AN: 3628

South Asian (SAS) AF: 0.00 AC: 0 AN: 3256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61672

Other (OTH) AF: 0.00 AC: 0 AN: 1826

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000989 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Fanconi anemia complementation group G (3)
-	2	-	Fanconi anemia (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.9
DANN	Benign	0.65
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.80
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.030
Sift	Benign	0.40	T
Sift4G	Benign	1.0	T
Polyphen		0.018	B
Vest4		0.17
MVP		0.46
MPC		0.21
ClinPred		0.037	T
GERP RS		1.4
Varity_R		0.014
gMVP		0.10
Mutation Taster		=96/4	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: rs375757497; hg19: chr9-35075739;