17-43213177-G-A

Position:

• chr17-43213177-G-A

Variant summary

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

The NM_145041.4(TMEM106A):​c.136G>A​(p.Val46Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,614,214 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (29 hom.)
• Consequence: TMEM106A NM_145041.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.400

Genes affected

TMEM106A (HGNC:28288): (transmembrane protein 106A) Predicted to be involved in several processes, including glycoprotein biosynthetic process; positive regulation of cytokine production; and positive regulation of intracellular signal transduction. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028369725).
• BP6: Variant 17-43213177-G-A is Benign according to our data. Variant chr17-43213177-G-A is described in ClinVar as [Benign]. Clinvar id is 777183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43213177-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00932 (1419/152320) while in subpopulation AFR AF= 0.0301 (1250/41568). AF 95% confidence interval is 0.0287. There are 17 homozygotes in gnomad4. There are 686 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM106A	NM_145041.4	c.136G>A	p.Val46Met	missense_variant	3/9	ENST00000612339.4	NP_659478.1
TMEM106A	NM_001291586.2	c.136G>A	p.Val46Met	missense_variant	3/9		NP_001278515.1
TMEM106A	NM_001291588.2	c.136G>A	p.Val46Met	missense_variant	2/7		NP_001278517.1
TMEM106A	NM_001291587.2	c.5-13G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001278516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM106A	ENST00000612339.4	c.136G>A	p.Val46Met	missense_variant	3/9	2	NM_145041.4	ENSP00000483246	P1

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1418 AN: 152202 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00264 AC: 664 AN: 251492 Hom.: 6 AF XY: 0.00190 AC XY: 258 AN XY: 135920

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00152 AC: 2217 AN: 1461894 Hom.: 29 Cov.: 31 AF XY: 0.00134 AC XY: 978 AN XY: 727248

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00932 AC: 1419 AN: 152320 Hom.: 17 Cov.: 32 AF XY: 0.00921 AC XY: 686 AN XY: 74478

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00189 Hom.: 2

Bravo AF: 0.0109

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.00287 AC: 348

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.0051	T;T;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.70	T;.;T;T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;.;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.32	.;.;N;.
REVEL	Benign	0.028
Sift	Benign	0.24	.;.;T;.
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.030	.;B;B;B
Vest4		0.21, 0.23
MVP		0.061
ClinPred		0.010	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.40

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: rs111480047; hg19: chr17-41365196;