12-95152845-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_018351.4(FGD6):c.2655-4A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,428 control chromosomes in the GnomAD database, including 22 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 0.0061 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (6 hom.)
• Consequence: FGD6 NM_018351.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0006705
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.950

Genes affected

FGD6 (HGNC:21740): (FYVE, RhoGEF and PH domain containing 6) Predicted to enable guanyl-nucleotide exchange factor activity and small GTPase binding activity. Predicted to be involved in several processes, including filopodium assembly; regulation of GTPase activity; and regulation of cell shape. Predicted to be located in Golgi apparatus; lamellipodium; and ruffle. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 12-95152845-T-A is Benign according to our data. Variant chr12-95152845-T-A is described in ClinVar as [Benign]. Clinvar id is 784253.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00607 (924/152162) while in subpopulation AFR AF= 0.0211 (875/41516). AF 95% confidence interval is 0.0199. There are 16 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD6	NM_018351.4	c.2655-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000343958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD6	ENST00000343958.9	c.2655-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018351.4	P1
FGD6	ENST00000549499.1	c.2655-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
FGD6	ENST00000451107.3	c.*50-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
FGD6	ENST00000546711.5	c.2655-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 912 AN: 152044 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00161 AC: 402 AN: 250212 Hom.: 8 AF XY: 0.00118 AC XY: 159 AN XY: 135318

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000602 AC: 880 AN: 1461266 Hom.: 6 Cov.: 31 AF XY: 0.000534 AC XY: 388 AN XY: 726940

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152162 Hom.: 16 Cov.: 32 AF XY: 0.00582 AC XY: 433 AN XY: 74402

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00176 Hom.: 3

Bravo AF: 0.00698

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	12
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00067
dbscSNV1_RF	Benign	0.032
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

Publications

LitVar

Other links and lift over

dbSNP: rs191808719; hg19: chr12-95546621;