7-112784096-T-G

Position:

• chr7-112784096-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022484.6(TMEM168):​c.730A>C​(p.Ser244Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM168 NM_022484.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

Genes affected

TMEM168 (HGNC:25826): (transmembrane protein 168) Located in transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]

LINC03076 (HGNC:56656): (long intergenic non-protein coding RNA 3076)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM168	NM_022484.6	c.730A>C	p.Ser244Arg	missense_variant	2/5	ENST00000312814.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM168	ENST00000312814.11	c.730A>C	p.Ser244Arg	missense_variant	2/5	1	NM_022484.6	P1
LINC03076	ENST00000656697.1	n.469-112257T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461046 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 01, 2022

The c.730A>C (p.S244R) alteration is located in exon 2 (coding exon 1) of the TMEM168 gene. This alteration results from a A to C substitution at nucleotide position 730, causing the serine (S) at amino acid position 244 to be replaced by an arginine (R). 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	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.027	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.96
MutPred		0.64		Loss of glycosylation at S244 (P = 0.0061);Loss of glycosylation at S244 (P = 0.0061);
MVP		0.45
MPC		0.48
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.63
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1793305807; hg19: chr7-112424151;