chr1-44001588-GCT-CCC

Variant names:

• chr1-44001588-GCT-CCC
• NM_001024845.3:c.1000_1002delAGCinsGGG
• SLC6A9 p.Ser334Gly

Variant summary

Our verdict is

Uncertain significance

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 5 ACMG points: 5P and 0B. PS1PP3

The NM_001024845.3(SLC6A9):​c.1000_1002delAGCinsGGG​(p.Ser334Gly) 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 Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S334S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC6A9 NM_001024845.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• Publications: 0 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, G2P, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_001024845.3 (SLC6A9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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_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.1000_1002delAGCinsGGG	p.Ser334Gly	missense	N/A	NP_001020016.1	P48067-2
	SLC6A9	NM_201649.4		c.1219_1221delAGCinsGGG	p.Ser407Gly	missense	N/A	NP_964012.2	P48067-1
	SLC6A9	NM_006934.4		c.1057_1059delAGCinsGGG	p.Ser353Gly	missense	N/A	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.1000_1002delAGCinsGGG	p.Ser334Gly	missense	N/A	ENSP00000361384.4	P48067-2
	SLC6A9	ENST00000360584.6	TSL:1	c.1219_1221delAGCinsGGG	p.Ser407Gly	missense	N/A	ENSP00000353791.2	P48067-1
	SLC6A9	ENST00000357730.6	TSL:1	c.1057_1059delAGCinsGGG	p.Ser353Gly	missense	N/A	ENSP00000350362.2	P48067-3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

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: chr1-44467260;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline