7-12231904-GAC-AAT

Variant names:

• chr7-12231904-GAC-AAT
• NM_001134232.2:c.754_756delGACinsAAT
• TMEM106B p.Asp252Asn

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_Very_Strong PM5 PP3

The NM_001134232.2(TMEM106B):​c.754_756delGACinsAAT​(p.Asp252Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: 9.56
• Publications: 0 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_001134232.2 (TMEM106B) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.754_756delGACinsAAT	p.Asp252Asn	missense	N/A	NP_001127704.1	Q9NUM4
	TMEM106B	NM_018374.4		c.754_756delGACinsAAT	p.Asp252Asn	missense	N/A	NP_060844.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	ENST00000396668.8	TSL:1 MANE Select	c.754_756delGACinsAAT	p.Asp252Asn	missense	N/A	ENSP00000379902.3	Q9NUM4
	TMEM106B	ENST00000396667.7	TSL:1	c.754_756delGACinsAAT	p.Asp252Asn	missense	N/A	ENSP00000379901.2	Q9NUM4
	TMEM106B	ENST00000444443.6	TSL:4	c.754_756delGACinsAAT	p.Asp252Asn	missense	N/A	ENSP00000401302.2	Q9NUM4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-12271530;