chr12-100387141-A-G

Variant names:

• chr12-100387141-A-G
• rs7485480
• NM_139319.3:c.355-3860A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139319.3(SLC17A8):​c.355-3860A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 152,132 control chromosomes in the GnomAD database, including 42,042 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42042 hom., cov: 32)
• Consequence: SLC17A8 NM_139319.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248
• Publications: 4 publications found

Genes affected

SLC17A8 (HGNC:20151): (solute carrier family 17 member 8) This gene encodes a vesicular glutamate transporter. The encoded protein transports the neurotransmitter glutamate into synaptic vesicles before it is released into the synaptic cleft. Mutations in this gene are the cause of autosomal-dominant nonsyndromic type 25 deafness. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

SLC17A8 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 25

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A8	NM_139319.3	c.355-3860A>G		intron_variant	Intron 2 of 11	ENST00000323346.10	NP_647480.1
SLC17A8	NM_001145288.2	c.355-3860A>G		intron_variant	Intron 2 of 10		NP_001138760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A8	ENST00000323346.10	c.355-3860A>G		intron_variant	Intron 2 of 11	1	NM_139319.3	ENSP00000316909.4
SLC17A8	ENST00000392989.3	c.355-3860A>G		intron_variant	Intron 2 of 10	1		ENSP00000376715.3

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112460 AN: 152014 Hom.: 42017 Cov.: 32

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.830

Gnomad ASJ AF: 0.818

Gnomad EAS AF: 0.952

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.742

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

GnomAD4 genome AF: 0.740 AC: 112533 AN: 152132 Hom.: 42042 Cov.: 32 AF XY: 0.742 AC XY: 55150 AN XY: 74354

African (AFR) AF: 0.701 AC: 29110 AN: 41498

American (AMR) AF: 0.830 AC: 12694 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 2835 AN: 3466

East Asian (EAS) AF: 0.952 AC: 4932 AN: 5178

South Asian (SAS) AF: 0.830 AC: 4002 AN: 4824

European-Finnish (FIN) AF: 0.697 AC: 7369 AN: 10572

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.724 AC: 49215 AN: 67992

Other (OTH) AF: 0.744 AC: 1566 AN: 2104

Alfa AF: 0.738 Hom.: 131311

Bravo AF: 0.750

Asia WGS AF: 0.854 AC: 2971 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.89
DANN	Benign	0.72
PhyloP100		0.25
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: rs7485480; hg19: chr12-100780919;