NM_032027.3:c.341G>T

Variant names:

• chr1-61709335-C-A
• rs369821446
• NM_032027.3:c.341G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032027.3(TM2D1):​c.341G>T​(p.Arg114Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R114Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TM2D1 NM_032027.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

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.341G>T	p.Arg114Leu	missense	Exon 3 of 7	NP_114416.1	Q9BX74
	TM2D1	NR_135160.2		n.362G>T		non_coding_transcript_exon	Exon 3 of 8
	TM2D1	NR_135161.2		n.362G>T		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D1	ENST00000606498.5	TSL:5 MANE Select	c.341G>T	p.Arg114Leu	missense	Exon 3 of 7	ENSP00000475700.1	Q9BX74
	TM2D1	ENST00000371180.7	TSL:5	c.341G>T	p.Arg114Leu	missense	Exon 3 of 7	ENSP00000360222.2	Q9BX74
	TM2D1	ENST00000371177.2	TSL:5	c.341G>T	p.Arg114Leu	missense	Exon 3 of 5	ENSP00000475297.1	U3KPW4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451948 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722796

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104040

Other (OTH) AF: 0.00 AC: 0 AN: 59972

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0054	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.25
Sift	Benign	0.064	T
Sift4G	Benign	0.17	T
Polyphen		0.86	P
Vest4		0.88
MutPred		0.46		Gain of ubiquitination at K109 (P = 0.1181)
MVP		0.38
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.36
gMVP		0.85
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369821446; hg19: chr1-62175007; COSMIC: COSV53906711;