2-70514916-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003236.4(TGFA):c.41-4A>G 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 0.000513 in 1,613,660 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: TGFA NM_003236.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.7986
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0370

Genes affected

TGFA (HGNC:11765): (transforming growth factor alpha) This gene encodes a growth factor that is a ligand for the epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. This protein may act as either a transmembrane-bound ligand or a soluble ligand. This gene has been associated with many types of cancers, and it may also be involved in some cases of cleft lip/palate. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-70514916-T-C is Benign according to our data. Variant chr2-70514916-T-C is described in ClinVar as [Benign]. Clinvar id is 714126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 436 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFA	NM_003236.4	c.41-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000295400.11
TGFA	NM_001099691.3	c.41-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TGFA	NM_001308158.2	c.59-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TGFA	NM_001308159.2	c.59-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFA	ENST00000295400.11	c.41-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003236.4	P4

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152120 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000813 AC: 203 AN: 249798 Hom.: 4 AF XY: 0.000496 AC XY: 67 AN XY: 134998

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000639

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000268 AC: 392 AN: 1461422 Hom.: 4 Cov.: 31 AF XY: 0.000206 AC XY: 150 AN XY: 726964

Gnomad4 AFR exome AF: 0.00950

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152238 Hom.: 3 Cov.: 32 AF XY: 0.00274 AC XY: 204 AN XY: 74434

Gnomad4 AFR AF: 0.00977

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00341

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

Nov 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	17
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11466221; hg19: chr2-70742048;