3-119447157-C-T

Variant names:

• chr3-119447157-C-T
• NM_018266.3:c.436G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018266.3(TMEM39A):​c.436G>A​(p.Ala146Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TMEM39A NM_018266.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

Genes affected

TMEM39A (HGNC:25600): (transmembrane protein 39A) Involved in negative regulation of autophagosome assembly; negative regulation of autophagosome maturation; and positive regulation of viral genome replication. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08676925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM39A	NM_018266.3	c.436G>A	p.Ala146Thr	missense_variant	Exon 5 of 9	ENST00000319172.10	NP_060736.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM39A	ENST00000319172.10	c.436G>A	p.Ala146Thr	missense_variant	Exon 5 of 9	1	NM_018266.3	ENSP00000326063.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459768 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.436G>A (p.A146T) alteration is located in exon 5 (coding exon 4) of the TMEM39A gene. This alteration results from a G to A substitution at nucleotide position 436, causing the alanine (A) at amino acid position 146 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	0.062
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0022	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.27	N;N
REVEL	Benign	0.048
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.28
MutPred		0.38		Loss of ubiquitination at K143 (P = 0.1498);Loss of ubiquitination at K143 (P = 0.1498);
MVP		0.068
MPC		0.35
ClinPred		0.84	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: chr3-119166004;