5-110625287-C-T

Position:

• chr5-110625287-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039763.4(TMEM232):​c.748G>A​(p.Glu250Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TMEM232 NM_001039763.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.334

Genes affected

TMEM232 (HGNC:37270): (transmembrane protein 232) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034143925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM232	NM_001039763.4	c.748G>A	p.Glu250Lys	missense_variant	7/14	ENST00000455884.7	NP_001034852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM232	ENST00000455884.7	c.748G>A	p.Glu250Lys	missense_variant	7/14	2	NM_001039763.4	ENSP00000401477.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2023

The c.748G>A (p.E250K) alteration is located in exon 7 (coding exon 6) of the TMEM232 gene. This alteration results from a G to A substitution at nucleotide position 748, causing the glutamic acid (E) at amino acid position 250 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.6
DANN	Benign	0.23
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.021
Sift	Benign	0.85	T
Sift4G	Benign	0.72	T
Polyphen		0.0020	B
Vest4		0.089
MutPred		0.22		Gain of ubiquitination at E250 (P = 0.0117);
MVP		0.014
ClinPred		0.054	T
GERP RS		-0.45
Varity_R		0.034
gMVP		0.082

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

Publications

LitVar

Other links and lift over

dbSNP: rs1784275187; hg19: chr5-109960988;