rs587118

Variant names:

• chr9-35074920-T-C
• rs587118
• NM_004629.2:c.1636+7A>G

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.1636+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,613,706 control chromosomes in the GnomAD database, including 171,513 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (12186 hom., cov: 32)
  • Exomes 𝑓: 0.45 (159327 hom.)
• Consequence: FANCG NM_004629.2 splice_region, intron
• Scores: Splicing: ADA: 0.00009051
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.479
• 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 (BayesDel_noAF=-0.65).
• BP6: Variant 9-35074920-T-C is Benign according to our data. Variant chr9-35074920-T-C is described in ClinVar as Benign. ClinVar VariationId is 259477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.492 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.1636+7A>G		splice_region intron	N/A	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.1636+7A>G		splice_region intron	N/A	ENSP00000367910.4	O15287
	FANCG	ENST00000425676.5	TSL:1	n.*1112+7A>G		splice_region intron	N/A	ENSP00000412793.1	F8WC08
	FANCG	ENST00000448890.2	TSL:3	c.1636+7A>G		splice_region intron	N/A	ENSP00000409607.2	O15287

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53601 AN: 152010 Hom.: 12180 Cov.: 32

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.392

GnomAD2 exomes AF: 0.402 AC: 100982 AN: 251416 AF XY: 0.403

Gnomad AFR exome AF: 0.0803

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.00321

Gnomad FIN exome AF: 0.502

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.452 AC: 660467 AN: 1461578 Hom.: 159327 Cov.: 45 AF XY: 0.448 AC XY: 325966 AN XY: 727106

African (AFR) AF: 0.0767 AC: 2569 AN: 33478

American (AMR) AF: 0.495 AC: 22127 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 9703 AN: 26134

East Asian (EAS) AF: 0.00406 AC: 161 AN: 39700

South Asian (SAS) AF: 0.263 AC: 22664 AN: 86244

European-Finnish (FIN) AF: 0.500 AC: 26708 AN: 53396

Middle Eastern (MID) AF: 0.368 AC: 2119 AN: 5762

European-Non Finnish (NFE) AF: 0.495 AC: 549927 AN: 1111750

Other (OTH) AF: 0.406 AC: 24489 AN: 60390

GnomAD4 genome AF: 0.352 AC: 53603 AN: 152128 Hom.: 12186 Cov.: 32 AF XY: 0.350 AC XY: 26015 AN XY: 74348

African (AFR) AF: 0.0909 AC: 3775 AN: 41534

American (AMR) AF: 0.458 AC: 6997 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1287 AN: 3470

East Asian (EAS) AF: 0.00540 AC: 28 AN: 5184

South Asian (SAS) AF: 0.235 AC: 1133 AN: 4824

European-Finnish (FIN) AF: 0.505 AC: 5325 AN: 10552

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33755 AN: 67970

Other (OTH) AF: 0.387 AC: 815 AN: 2106

Alfa AF: 0.455 Hom.: 24407

Bravo AF: 0.338

Asia WGS AF: 0.137 AC: 481 AN: 3478

EpiCase AF: 0.487

EpiControl AF: 0.494

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fanconi anemia complementation group G (5)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)
-	-	1	Amyotrophic Lateral Sclerosis, Dominant (1)
-	-	1	Inclusion Body Myopathy, Dominant (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.8
DANN	Benign	0.81
PhyloP100		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000091
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.070		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: rs587118; hg19: chr9-35074917; COSMIC: COSV62719986; COSMIC: COSV62719986;