1-61723731-T-A

Variant names:

• chr1-61723731-T-A
• rs1232427248
• NM_032027.3:c.220A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032027.3(TM2D1):​c.220A>T​(p.Thr74Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,407,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. T74A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TM2D1 NM_032027.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3120771).

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.220A>T	p.Thr74Ser	missense	Exon 2 of 7	NP_114416.1	Q9BX74
	TM2D1	NR_135160.2		n.241A>T		non_coding_transcript_exon	Exon 2 of 8
	TM2D1	NR_135161.2		n.241A>T		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D1	ENST00000606498.5	TSL:5 MANE Select	c.220A>T	p.Thr74Ser	missense	Exon 2 of 7	ENSP00000475700.1	Q9BX74
	TM2D1	ENST00000371180.7	TSL:5	c.220A>T	p.Thr74Ser	missense	Exon 2 of 7	ENSP00000360222.2	Q9BX74
	TM2D1	ENST00000371177.2	TSL:5	c.220A>T	p.Thr74Ser	missense	Exon 2 of 5	ENSP00000475297.1	U3KPW4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407584 Hom.: 0 Cov.: 25 AF XY: 0.00000143 AC XY: 1 AN XY: 696908

⚠️ 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: 32384

American (AMR) AF: 0.00 AC: 0 AN: 39574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 38652

South Asian (SAS) AF: 0.00 AC: 0 AN: 78024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078626

Other (OTH) AF: 0.00 AC: 0 AN: 58300

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0098	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.073
Sift	Benign	0.32	T
Sift4G	Benign	0.32	T
Polyphen		0.69	P
Vest4		0.52
MutPred		0.24		Loss of sheet (P = 0.0817)
MVP		0.45
MPC		0.26
ClinPred		0.66	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.42
Mutation Taster		=80/20	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: rs1232427248; hg19: chr1-62189403;