chr1-43997498-G-A

Variant names:

• chr1-43997498-G-A
• rs2248253
• NM_001024845.3:c.*47C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001024845.3(SLC6A9):​c.*47C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 1,549,872 control chromosomes in the GnomAD database, including 7,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1595 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5899 hom.)
• Consequence: SLC6A9 NM_001024845.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.801
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-43997498-G-A is Benign according to our data. Variant chr1-43997498-G-A is described in ClinVar as Benign. ClinVar VariationId is 1242659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A9	NM_001024845.3	c.*47C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000372310.8	NP_001020016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A9	ENST00000372310.8	c.*47C>T		3_prime_UTR_variant	Exon 14 of 14	5	NM_001024845.3	ENSP00000361384.4

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18940 AN: 152032 Hom.: 1591 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.0960

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.106 AC: 25091 AN: 237020 AF XY: 0.102

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.0708

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0825 AC: 115329 AN: 1397720 Hom.: 5899 Cov.: 24 AF XY: 0.0822 AC XY: 57420 AN XY: 698510

African (AFR) AF: 0.238 AC: 7563 AN: 31824

American (AMR) AF: 0.147 AC: 6194 AN: 42178

Ashkenazi Jewish (ASJ) AF: 0.0714 AC: 1815 AN: 25412

East Asian (EAS) AF: 0.188 AC: 7396 AN: 39396

South Asian (SAS) AF: 0.108 AC: 9149 AN: 84912

European-Finnish (FIN) AF: 0.114 AC: 5891 AN: 51596

Middle Eastern (MID) AF: 0.127 AC: 633 AN: 4998

European-Non Finnish (NFE) AF: 0.0673 AC: 71267 AN: 1059314

Other (OTH) AF: 0.0933 AC: 5421 AN: 58090

GnomAD4 genome AF: 0.125 AC: 18965 AN: 152152 Hom.: 1595 Cov.: 32 AF XY: 0.126 AC XY: 9381 AN XY: 74386

African (AFR) AF: 0.229 AC: 9516 AN: 41478

American (AMR) AF: 0.120 AC: 1830 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3470

East Asian (EAS) AF: 0.151 AC: 778 AN: 5166

South Asian (SAS) AF: 0.0965 AC: 465 AN: 4820

European-Finnish (FIN) AF: 0.125 AC: 1320 AN: 10602

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0661 AC: 4491 AN: 67990

Other (OTH) AF: 0.116 AC: 246 AN: 2114

Alfa AF: 0.0998 Hom.: 292

Bravo AF: 0.130

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.80
Mutation Taster		=100/0	polymorphism (auto)

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: rs2248253; hg19: chr1-44463170; COSMIC: COSV107437660; COSMIC: COSV107437660;