19-16661335-G-C

Position:

• chr19-16661335-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024074.4(TMEM38A):​c.118G>C​(p.Glu40Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM38A NM_024074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

Genes affected

TMEM38A (HGNC:28462): (transmembrane protein 38A) Predicted to enable potassium channel activity. Predicted to act upstream of or within several processes, including cellular response to caffeine; inorganic cation transmembrane transport; and regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TMEM38A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34300503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM38A	NM_024074.4	c.118G>C	p.Glu40Gln	missense_variant	1/6	ENST00000187762.7	NP_076979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM38A	ENST00000187762.7	c.118G>C	p.Glu40Gln	missense_variant	1/6	1	NM_024074.4	ENSP00000187762.1
TMEM38A	ENST00000599479.1	c.73G>C	p.Glu25Gln	missense_variant	1/4	3		ENSP00000469721.1
TMEM38A	ENST00000595452.1	n.94G>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 23, 2024

The c.118G>C (p.E40Q) alteration is located in exon 1 (coding exon 1) of the TMEM38A gene. This alteration results from a G to C substitution at nucleotide position 118, causing the glutamic acid (E) at amino acid position 40 to be replaced by a glutamine (Q). 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	0.26
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.024
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.80	P
Vest4		0.54
MutPred		0.42		Gain of ubiquitination at K38 (P = 0.078);
MVP		0.10
MPC		0.96
ClinPred		0.80	D
GERP RS		3.5
Varity_R		0.28
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-16772146;