5-110528675-T-G

Variant names:

• chr5-110528675-T-G
• rs934914111
• NM_001039763.4:c.1616A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001039763.4(TMEM232):​c.1616A>C​(p.Lys539Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,535,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TMEM232 NM_001039763.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• Publications: 0 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.12526381).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM232	NM_001039763.4	c.1616A>C	p.Lys539Thr	missense_variant	Exon 12 of 14	ENST00000455884.7	NP_001034852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM232	ENST00000455884.7	c.1616A>C	p.Lys539Thr	missense_variant	Exon 12 of 14	2	NM_001039763.4	ENSP00000401477.2
TMEM232	ENST00000512003.7	n.*997+39772A>C		intron_variant	Intron 9 of 10	1		ENSP00000427785.2
TMEM232	ENST00000515518.6	n.1375+39772A>C		intron_variant	Intron 10 of 12	1
TMEM232	ENST00000508571.6	n.1018+39772A>C		intron_variant	Intron 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000671 AC: 9 AN: 134044 AF XY: 0.0000137

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000243

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1383078 Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 2 AN XY: 682486

African (AFR) AF: 0.0000317 AC: 1 AN: 31572

American (AMR) AF: 0.000308 AC: 11 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 35600

South Asian (SAS) AF: 0.00 AC: 0 AN: 79158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078522

Other (OTH) AF: 0.0000346 AC: 2 AN: 57844

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.000262 AC: 4 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000144

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1616A>C (p.K539T) alteration is located in exon 12 (coding exon 11) of the TMEM232 gene. This alteration results from a A to C substitution at nucleotide position 1616, causing the lysine (K) at amino acid position 539 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.7
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.083
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.031	D
Polyphen		0.50	P
Vest4		0.16
MutPred		0.33		Loss of methylation at K539 (P = 0.0023);
MVP		0.030
ClinPred		0.10	T
GERP RS		5.3
Varity_R		0.23
gMVP		0.041
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs934914111; hg19: chr5-109864376;