1-1918348-G-A

Variant names:

• chr1-1918348-G-A
• rs199968298
• NM_178545.4:c.254C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178545.4(TMEM52):​c.254C>T​(p.Ala85Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A85E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM52 NM_178545.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 0 publications found

Genes affected

TMEM52 (HGNC:27916): (transmembrane protein 52) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03834021).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178545.4. 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
	TMEM52	NM_178545.4	MANE Select	c.254C>T	p.Ala85Val	missense	Exon 4 of 5	NP_848640.1	Q8NDY8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM52	ENST00000310991.8	TSL:1 MANE Select	c.254C>T	p.Ala85Val	missense	Exon 4 of 5	ENSP00000311122.3	Q8NDY8-1
	TMEM52	ENST00000378602.3	TSL:1	c.209C>T	p.Ala70Val	missense	Exon 1 of 2	ENSP00000367865.3	Q8NDY8-2
	TMEM52	ENST00000902364.1		c.272C>T	p.Ala91Val	missense	Exon 4 of 5	ENSP00000572423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460592 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.086
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.053
Sift	Benign	0.81	T
Sift4G	Benign	0.47	T
Polyphen		0.050	B
Vest4		0.074
MutPred		0.25		Loss of disorder (P = 0.0665)
MVP		0.17
MPC		0.046
ClinPred		0.072	T
GERP RS		-3.1
PromoterAI		-0.068	Neutral
Varity_R		0.022
gMVP		0.20
Mutation Taster		=95/5	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: rs199968298; hg19: chr1-1849787;