rs778917284

Variant names:

• chr1-61700997-C-A
• NM_032027.3:c.376G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-61700997-C-A
• chr1-61700997-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032027.3(TM2D1):​c.376G>T​(p.Ala126Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,282 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TM2D1 NM_032027.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D1	NM_032027.3	c.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 7	ENST00000606498.5	NP_114416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM2D1	ENST00000606498.5	c.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 7	5	NM_032027.3	ENSP00000475700.1
TM2D1	ENST00000371180.7	c.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 7	5		ENSP00000360222.2
TM2D1	ENST00000371177.2	c.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 5	5		ENSP00000475297.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456282 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724354

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: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L;L;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	.;N;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.38	.;T;T;.
Sift4G	Benign	0.41	T;T;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.77
MutPred		0.55		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);
MVP		0.58
MPC		0.88
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: chr1-62166669;