1-61725063-C-T

Variant names:

• chr1-61725063-C-T
• NM_032027.3:c.58G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032027.3(TM2D1):​c.58G>A​(p.Val20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TM2D1 NM_032027.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.186

Genes affected

TM2D1 (HGNC:24142): (TM2 domain containing 1) The protein encoded by this gene is a beta-amyloid peptide-binding protein. It contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily and known to be important in heterotrimeric G protein activation. Beta-amyloid peptide has been established to be a causative factor in neuron death and the consequent diminution of cognitive abilities observed in Alzheimer's disease. This protein may be a target of neurotoxic beta-amyloid peptide, and may mediate cellular vulnerability to beta-amyloid peptide toxicity through a G protein-regulated program of cell death. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053445995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D1	NM_032027.3	c.58G>A	p.Val20Ile	missense_variant	Exon 1 of 7	ENST00000606498.5	NP_114416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM2D1	ENST00000606498.5	c.58G>A	p.Val20Ile	missense_variant	Exon 1 of 7	5	NM_032027.3	ENSP00000475700.1
TM2D1	ENST00000371180.7	c.58G>A	p.Val20Ile	missense_variant	Exon 1 of 7	5		ENSP00000360222.2
TM2D1	ENST00000371177.2	c.58G>A	p.Val20Ile	missense_variant	Exon 1 of 5	5		ENSP00000475297.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727062

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58G>A (p.V20I) alteration is located in exon 1 (coding exon 1) of the TM2D1 gene. This alteration results from a G to A substitution at nucleotide position 58, causing the valine (V) at amino acid position 20 to be replaced by an isoleucine (I). 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	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.56
DANN	Benign	0.89
DEOGEN2	Benign	0.0058	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.70	.;T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.17	.;N;N;.
REVEL	Benign	0.0
Sift	Benign	0.53	.;T;T;.
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.0050	B;B;.;.
Vest4		0.16
MutPred		0.22		Loss of MoRF binding (P = 0.1124);Loss of MoRF binding (P = 0.1124);.;Loss of MoRF binding (P = 0.1124);
MVP		0.13
MPC		0.21
ClinPred		0.032	T
GERP RS		-0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.44

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: chr1-62190735;