chr1-44002315-G-A

Variant names:

• chr1-44002315-G-A
• rs61733181
• NM_001024845.3:c.960C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001024845.3(SLC6A9):​c.960C>T​(p.Tyr320Tyr) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00878 in 1,610,120 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (115 hom.)
• Consequence: SLC6A9 NM_001024845.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9521
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.78
• Publications: 6 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: AR, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-44002315-G-A is Benign according to our data. Variant chr1-44002315-G-A is described in ClinVar as Benign. ClinVar VariationId is 476370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0112 (1713/152290) while in subpopulation SAS AF = 0.028 (135/4828). AF 95% confidence interval is 0.0241. There are 18 homozygotes in GnomAd4. There are 870 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A9	NM_001024845.3	MANE Select	c.960C>T	p.Tyr320Tyr	splice_region synonymous	Exon 8 of 14	NP_001020016.1
	SLC6A9	NM_201649.4		c.1179C>T	p.Tyr393Tyr	splice_region synonymous	Exon 8 of 14	NP_964012.2
	SLC6A9	NM_006934.4		c.1017C>T	p.Tyr339Tyr	splice_region synonymous	Exon 7 of 13	NP_008865.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A9	ENST00000372310.8	TSL:5 MANE Select	c.960C>T	p.Tyr320Tyr	splice_region synonymous	Exon 8 of 14	ENSP00000361384.4
	SLC6A9	ENST00000360584.6	TSL:1	c.1179C>T	p.Tyr393Tyr	splice_region synonymous	Exon 8 of 14	ENSP00000353791.2
	SLC6A9	ENST00000357730.6	TSL:1	c.1017C>T	p.Tyr339Tyr	splice_region synonymous	Exon 7 of 13	ENSP00000350362.2

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1706 AN: 152172 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00944 AC: 2373 AN: 251374 AF XY: 0.0104

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00752

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00852 AC: 12425 AN: 1457830 Hom.: 115 Cov.: 31 AF XY: 0.00898 AC XY: 6511 AN XY: 725450

African (AFR) AF: 0.0244 AC: 815 AN: 33408

American (AMR) AF: 0.00266 AC: 119 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0267 AC: 2303 AN: 86146

European-Finnish (FIN) AF: 0.00522 AC: 279 AN: 53406

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5760

European-Non Finnish (NFE) AF: 0.00740 AC: 8207 AN: 1108372

Other (OTH) AF: 0.00933 AC: 562 AN: 60254

GnomAD4 genome AF: 0.0112 AC: 1713 AN: 152290 Hom.: 18 Cov.: 32 AF XY: 0.0117 AC XY: 870 AN XY: 74472

African (AFR) AF: 0.0233 AC: 969 AN: 41550

American (AMR) AF: 0.00294 AC: 45 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4828

European-Finnish (FIN) AF: 0.00536 AC: 57 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00697 AC: 474 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00929 Hom.: 8

Bravo AF: 0.0109

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Atypical glycine encephalopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.52
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: rs61733181; hg19: chr1-44467987; COSMIC: COSV107437657;