rs1554310600

Variant names:

• chr7-12231904-G-A
• rs1554310600
• NM_001134232.2:c.754G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001134232.2(TMEM106B):​c.754G>A​(p.Asp252Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM106B NM_001134232.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.56
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-12231904-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3772686.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 7-12231904-G-A is Pathogenic according to our data. Variant chr7-12231904-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 523236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	NM_001134232.2	MANE Select	c.754G>A	p.Asp252Asn	missense	Exon 8 of 8	NP_001127704.1	Q9NUM4
	TMEM106B	NM_018374.4		c.754G>A	p.Asp252Asn	missense	Exon 9 of 9	NP_060844.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	ENST00000396668.8	TSL:1 MANE Select	c.754G>A	p.Asp252Asn	missense	Exon 8 of 8	ENSP00000379902.3	Q9NUM4
	TMEM106B	ENST00000396667.7	TSL:1	c.754G>A	p.Asp252Asn	missense	Exon 9 of 9	ENSP00000379901.2	Q9NUM4
	TMEM106B	ENST00000444443.6	TSL:4	c.754G>A	p.Asp252Asn	missense	Exon 8 of 8	ENSP00000401302.2	Q9NUM4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Leukodystrophy, hypomyelinating, 16 (9)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.53
Sift	Benign	0.054	T
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.93		Gain of loop (P = 0.0502)
MVP		0.55
MPC		0.87
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.67
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554310600; hg19: chr7-12271530; COSMIC: COSV67543986; COSMIC: COSV67543986;