9-100473659-G-A

Variant names:

• chr9-100473659-G-A
• NM_003692.5:c.115G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003692.5(TMEFF1):​c.115G>A​(p.Ala39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEFF1 NM_003692.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

Genes affected

TMEFF1 (HGNC:11866): (transmembrane protein with EGF like and two follistatin like domains 1) Predicted to enable signaling receptor binding activity. Predicted to be involved in animal organ morphogenesis; neuron projection development; and tissue development. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MSANTD3-TMEFF1 (HGNC:38838): (MSANTD3-TMEFF1 readthrough) This locus represents naturally occurring read-through transcription from the neighboring MSANTD3 (Myb/SANT-like DNA-binding domain containing 3) and TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1) genes. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36280388).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEFF1	NM_003692.5	c.115G>A	p.Ala39Thr	missense_variant	Exon 1 of 10	ENST00000374879.5	NP_003683.2
MSANTD3-TMEFF1	NM_001198812.1	c.419-25106G>A		intron_variant	Intron 1 of 9		NP_001185741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEFF1	ENST00000374879.5	c.115G>A	p.Ala39Thr	missense_variant	Exon 1 of 10	1	NM_003692.5	ENSP00000364013.4
MSANTD3-TMEFF1	ENST00000502978.1	c.80-25106G>A		intron_variant	Intron 1 of 9	2		ENSP00000424768.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115G>A (p.A39T) alteration is located in exon 1 (coding exon 1) of the TMEFF1 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the alanine (A) at amino acid position 39 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.043
Eigen_PC	Benign	0.0065
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.11
Sift	Benign	0.36	T
Sift4G	Benign	0.59	T
Polyphen		0.96	D
Vest4		0.12
MutPred		0.15		Gain of phosphorylation at A39 (P = 0.0373);
MVP		0.66
MPC		0.58
ClinPred		0.87	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-103235941;