4-163519376-G-A

Variant names:

• chr4-163519376-G-A
• rs1737934169
• NM_018352.3:c.474G>A

Variant summary

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

The NM_018352.3(TMA16):​c.474G>A​(p.Met158Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,126 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMA16 NM_018352.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

Genes affected

TMA16 (HGNC:25638): (translation machinery associated 16 homolog) Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.4063572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMA16	NM_018352.3	c.474G>A	p.Met158Ile	missense_variant	Exon 7 of 7	ENST00000358572.10	NP_060822.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMA16	ENST00000358572.10	c.474G>A	p.Met158Ile	missense_variant	Exon 7 of 7	1	NM_018352.3	ENSP00000351380.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452126 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 722172

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: 0.00000271

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

Oct 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.474G>A (p.M158I) alteration is located in exon 7 (coding exon 7) of the TMA16 gene. This alteration results from a G to A substitution at nucleotide position 474, causing the methionine (M) at amino acid position 158 to be replaced by an isoleucine (I). 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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.17
Sift	Benign	0.10	T
Sift4G	Uncertain	0.059	T
Polyphen		0.98	D
Vest4		0.46
MutPred		0.61		Gain of methylation at K157 (P = 0.0299);
MVP		0.54
MPC		0.24
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.42
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs1737934169; hg19: chr4-164440528; COSMIC: COSV99922107; COSMIC: COSV99922107;