7-12224099-T-A

Variant names:

• chr7-12224099-T-A
• rs17165746
• NM_001134232.2:c.282-127T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134232.2(TMEM106B):​c.282-127T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 808,874 control chromosomes in the GnomAD database, including 5,162 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1376 hom., cov: 32)
  • Exomes 𝑓: 0.10 (3786 hom.)
• Consequence: TMEM106B NM_001134232.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 4 publications found

Genes affected

TMEM106B (HGNC:22407): (transmembrane protein 106B) Enables ATPase binding activity. Involved in dendrite morphogenesis and lysosome localization. Located in endosome and lysosomal membrane. Implicated in hypomyelinating leukodystrophy. [provided by Alliance of Genome Resources, Apr 2022]

TMEM106B Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 16

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134232.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	NM_001134232.2	MANE Select	c.282-127T>A		intron	N/A	NP_001127704.1
	TMEM106B	NM_018374.4		c.282-127T>A		intron	N/A	NP_060844.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	ENST00000396668.8	TSL:1 MANE Select	c.282-127T>A		intron	N/A	ENSP00000379902.3
	TMEM106B	ENST00000396667.7	TSL:1	c.282-127T>A		intron	N/A	ENSP00000379901.2
	TMEM106B	ENST00000420833.5	TSL:1	n.*168-127T>A		intron	N/A	ENSP00000391016.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19239 AN: 152100 Hom.: 1374 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0883

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0956

Gnomad OTH AF: 0.122

GnomAD4 exome AF: 0.101 AC: 66390 AN: 656656 Hom.: 3786 AF XY: 0.103 AC XY: 35038 AN XY: 341702

African (AFR) AF: 0.193 AC: 3264 AN: 16882

American (AMR) AF: 0.0933 AC: 2740 AN: 29382

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 1650 AN: 15152

East Asian (EAS) AF: 0.0713 AC: 2518 AN: 35330

South Asian (SAS) AF: 0.158 AC: 8026 AN: 50844

European-Finnish (FIN) AF: 0.111 AC: 5016 AN: 45202

Middle Eastern (MID) AF: 0.103 AC: 400 AN: 3866

European-Non Finnish (NFE) AF: 0.0919 AC: 39288 AN: 427316

Other (OTH) AF: 0.107 AC: 3488 AN: 32682

GnomAD4 genome AF: 0.126 AC: 19252 AN: 152218 Hom.: 1376 Cov.: 32 AF XY: 0.126 AC XY: 9374 AN XY: 74436

African (AFR) AF: 0.196 AC: 8146 AN: 41518

American (AMR) AF: 0.101 AC: 1548 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3472

East Asian (EAS) AF: 0.0885 AC: 459 AN: 5184

South Asian (SAS) AF: 0.160 AC: 771 AN: 4824

European-Finnish (FIN) AF: 0.105 AC: 1110 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0956 AC: 6500 AN: 67998

Other (OTH) AF: 0.122 AC: 257 AN: 2114

Alfa AF: 0.108 Hom.: 132

Bravo AF: 0.126

Asia WGS AF: 0.114 AC: 397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.44
DANN	Benign	0.87
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17165746; hg19: chr7-12263725; COSMIC: COSV67543524;