3-119437901-T-C

Variant names:

• chr3-119437901-T-C
• rs146106236
• NM_018266.3:c.778A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018266.3(TMEM39A):​c.778A>G​(p.Thr260Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,613,572 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: TMEM39A NM_018266.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040200144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM39A	NM_018266.3	c.778A>G	p.Thr260Ala	missense_variant	Exon 6 of 9	ENST00000319172.10	NP_060736.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM39A	ENST00000319172.10	c.778A>G	p.Thr260Ala	missense_variant	Exon 6 of 9	1	NM_018266.3	ENSP00000326063.5

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 151998 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000390 AC: 98 AN: 251342 AF XY: 0.000456

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000560 AC: 818 AN: 1461456 Hom.: 1 Cov.: 31 AF XY: 0.000605 AC XY: 440 AN XY: 726952

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44708

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.000606 AC: 674 AN: 1111642

Other (OTH) AF: 0.000447 AC: 27 AN: 60384

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74368

African (AFR) AF: 0.000217 AC: 9 AN: 41490

American (AMR) AF: 0.000131 AC: 2 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67994

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.000332

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.778A>G (p.T260A) alteration is located in exon 6 (coding exon 5) of the TMEM39A gene. This alteration results from a A to G substitution at nucleotide position 778, causing the threonine (T) at amino acid position 260 to be replaced by an alanine (A). 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	-0.44	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		3.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.048
Sift	Benign	0.13	T;.
Sift4G	Benign	0.20	T;.
Polyphen		0.041	B;.
Vest4		0.33
MVP		0.068
MPC		0.37
ClinPred		0.023	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.051
gMVP		0.35
Mutation Taster		=84/16	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: rs146106236; hg19: chr3-119156748;