chr1-61700997-C-A

Variant names:

• chr1-61700997-C-A
• rs778917284
• NM_032027.3:c.376G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032027.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D1	NM_032027.3	MANE Select	c.376G>T	p.Ala126Ser	missense	Exon 4 of 7	NP_114416.1	Q9BX74
	TM2D1	NR_135160.2		n.397G>T		non_coding_transcript_exon	Exon 4 of 8
	TM2D1	NR_135161.2		n.397G>T		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D1	ENST00000606498.5	TSL:5 MANE Select	c.376G>T	p.Ala126Ser	missense	Exon 4 of 7	ENSP00000475700.1	Q9BX74
	TM2D1	ENST00000371180.7	TSL:5	c.376G>T	p.Ala126Ser	missense	Exon 4 of 7	ENSP00000360222.2	Q9BX74
	TM2D1	ENST00000371177.2	TSL:5	c.376G>T	p.Ala126Ser	missense	Exon 4 of 5	ENSP00000475297.1	U3KPW4

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

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39402

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109040

Other (OTH) AF: 0.00 AC: 0 AN: 60096

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.42
Sift	Benign	0.38	T
Sift4G	Benign	0.41	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.55		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
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs778917284; hg19: chr1-62166669;