rs1057519314

Variant names:

• chr1-44000805-G-A
• rs1057519314
• NM_001024845.3:c.1498C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001024845.3(SLC6A9):​c.1498C>T​(p.Gln500*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC6A9 NM_001024845.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.55
• Publications: 3 publications found

Genes affected

SLC6A9 (HGNC:11056): (solute carrier family 6 member 9) The amino acid glycine acts as an inhibitory neurotransmitter in the central nervous system. The protein encoded by this gene is one of two transporters that stop glycine signaling by removing it from the synaptic cleft. [provided by RefSeq, Jun 2016]

SLC6A9 Gene-Disease associations (from GenCC):

• atypical glycine encephalopathy

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-44000805-G-A is Pathogenic according to our data. Variant chr1-44000805-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 374987.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024845.3. 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
	SLC6A9	NM_001024845.3	MANE Select	c.1498C>T	p.Gln500*	stop_gained	Exon 12 of 14	NP_001020016.1	P48067-2
	SLC6A9	NM_201649.4		c.1717C>T	p.Gln573*	stop_gained	Exon 12 of 14	NP_964012.2	P48067-1
	SLC6A9	NM_006934.4		c.1555C>T	p.Gln519*	stop_gained	Exon 11 of 13	NP_008865.2	P48067-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A9	ENST00000372310.8	TSL:5 MANE Select	c.1498C>T	p.Gln500*	stop_gained	Exon 12 of 14	ENSP00000361384.4	P48067-2
	SLC6A9	ENST00000360584.6	TSL:1	c.1717C>T	p.Gln573*	stop_gained	Exon 12 of 14	ENSP00000353791.2	P48067-1
	SLC6A9	ENST00000357730.6	TSL:1	c.1555C>T	p.Gln519*	stop_gained	Exon 11 of 13	ENSP00000350362.2	P48067-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Atypical glycine encephalopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.5
Vest4		0.83
ClinPred		0.98	D
GERP RS		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519314; hg19: chr1-44466477;