chr2-70456379-C-T

Position:

• chr2-70456379-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000295400.11(TGFA):​c.325G>A​(p.Val109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,572,908 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: TGFA ENST00000295400.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.49

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004414737).
• BP6: Variant 2-70456379-C-T is Benign according to our data. Variant chr2-70456379-C-T is described in ClinVar as [Benign]. Clinvar id is 709603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1678/152332) while in subpopulation AFR AF= 0.0373 (1549/41568). AF 95% confidence interval is 0.0357. There are 34 homozygotes in gnomad4. There are 770 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1678 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFA	NM_003236.4	c.325G>A	p.Val109Met	missense_variant	4/6	ENST00000295400.11	NP_003227.1
TGFA	NM_001308158.2	c.343G>A	p.Val115Met	missense_variant	4/6		NP_001295087.1
TGFA	NM_001308159.2	c.340G>A	p.Val114Met	missense_variant	4/6		NP_001295088.1
TGFA	NM_001099691.3	c.322G>A	p.Val108Met	missense_variant	4/6		NP_001093161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFA	ENST00000295400.11	c.325G>A	p.Val109Met	missense_variant	4/6	1	NM_003236.4	ENSP00000295400	P4

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1675 AN: 152214 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

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: 0.000235

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00260 AC: 485 AN: 186612 Hom.: 7 AF XY: 0.00195 AC XY: 194 AN XY: 99612

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000372

Gnomad SAS exome AF: 0.000124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.000409

GnomAD4 exome AF: 0.00112 AC: 1587 AN: 1420576 Hom.: 28 Cov.: 31 AF XY: 0.000952 AC XY: 669 AN XY: 702820

Gnomad4 AFR exome AF: 0.0388

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000108

Gnomad4 SAS exome AF: 0.0000994

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.0000743

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.0110 AC: 1678 AN: 152332 Hom.: 34 Cov.: 33 AF XY: 0.0103 AC XY: 770 AN XY: 74484

Gnomad4 AFR AF: 0.0373

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00221 Hom.: 7

Bravo AF: 0.0130

ESP6500AA AF: 0.0329 AC: 145

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00255 AC: 308

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
MetaRNN	Benign	0.0044	T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	2.9	M;.;.;.;.;.
MutationTaster	Benign	0.51	N;N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.11	T;T;T;T;T;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.28
MVP		0.44
MPC		0.79
ClinPred		0.053	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs11466259; hg19: chr2-70683511; COSMIC: COSV99040073;