rs35276012

Positions:

• chr17-28358960-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152464.3(TMEM199):​c.256T>C​(p.Tyr86His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,612,660 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (14 hom.)
• Consequence: TMEM199 NM_152464.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.55

Genes affected

TMEM199 (HGNC:18085): (transmembrane protein 199) The protein encoded by this gene has been observed to localize to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and coat protein complex I (COPI) in some human cells. The encoded protein shares some homology with the yeast protein Vma12. Defects in this gene are a cause of congenital disorder of glycosylation, type IIp. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003996372).
• BP6: Variant 17-28358960-T-C is Benign according to our data. Variant chr17-28358960-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 445808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00628 (957/152364) while in subpopulation AFR AF= 0.0224 (931/41594). AF 95% confidence interval is 0.0212. There are 10 homozygotes in gnomad4. There are 448 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM199	NM_152464.3	c.256T>C	p.Tyr86His	missense_variant	2/6	ENST00000292114.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM199	ENST00000292114.8	c.256T>C	p.Tyr86His	missense_variant	2/6	1	NM_152464.3	P1

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 947 AN: 152246 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00168 AC: 420 AN: 249436 Hom.: 7 AF XY: 0.00119 AC XY: 160 AN XY: 134870

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.000529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000660 AC: 964 AN: 1460296 Hom.: 14 Cov.: 30 AF XY: 0.000573 AC XY: 416 AN XY: 726472

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.000655

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00628 AC: 957 AN: 152364 Hom.: 10 Cov.: 33 AF XY: 0.00601 AC XY: 448 AN XY: 74518

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00129 Hom.: 5

Bravo AF: 0.00710

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.47	N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.18
Sift	Benign	0.63	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.22
MVP		0.040
MPC		0.29
ClinPred		0.013	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35276012; hg19: chr17-26685983; COSMIC: COSV99060505; COSMIC: COSV99060505;