17-75283543-A-G

Variant names:

• chr17-75283543-A-G
• rs7213318
• NM_001126121.2:c.339T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001126121.2(SLC25A19):​c.339T>C​(p.Tyr113Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,613,560 control chromosomes in the GnomAD database, including 777,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67098 hom., cov: 30)
  • Exomes 𝑓: 0.99 (710666 hom.)
• Consequence: SLC25A19 NM_001126121.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0250
• Publications: 15 publications found

Genes affected

SLC25A19 (HGNC:14409): (solute carrier family 25 member 19) This gene encodes a mitochondrial protein that is a member of the solute carrier family. Although this protein was initially thought to be the mitochondrial deoxynucleotide carrier involved in the uptake of deoxynucleotides into the matrix of the mitochondria, further studies have demonstrated that this protein instead functions as the mitochondrial thiamine pyrophosphate carrier, which transports thiamine pyrophosphates into mitochondria. Mutations in this gene cause microcephaly, Amish type, a metabolic disease that results in severe congenital microcephaly, severe 2-ketoglutaric aciduria, and death within the first year. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

SLC25A19 Gene-Disease associations (from GenCC):

• Amish lethal microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• progressive demyelinating neuropathy with bilateral striatal necrosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 17-75283543-A-G is Benign according to our data. Variant chr17-75283543-A-G is described in ClinVar as Benign. ClinVar VariationId is 130330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126121.2. 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
	SLC25A19	NM_001126121.2	MANE Select	c.339T>C	p.Tyr113Tyr	synonymous	Exon 5 of 8	NP_001119593.1	Q9HC21-1
	SLC25A19	NM_001126122.2		c.339T>C	p.Tyr113Tyr	synonymous	Exon 4 of 7	NP_001119594.1	Q9HC21-1
	SLC25A19	NM_021734.5		c.339T>C	p.Tyr113Tyr	synonymous	Exon 5 of 8	NP_068380.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A19	ENST00000416858.7	TSL:1 MANE Select	c.339T>C	p.Tyr113Tyr	synonymous	Exon 5 of 8	ENSP00000397818.2	Q9HC21-1
	SLC25A19	ENST00000402418.7	TSL:1	c.339T>C	p.Tyr113Tyr	synonymous	Exon 3 of 6	ENSP00000385312.3	Q9HC21-1
	SLC25A19	ENST00000320362.7	TSL:2	c.339T>C	p.Tyr113Tyr	synonymous	Exon 6 of 9	ENSP00000319574.3	Q9HC21-1

Frequencies

GnomAD3 genomes AF: 0.936 AC: 142253 AN: 152042 Hom.: 67066 Cov.: 30

Gnomad AFR AF: 0.814

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.932

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.921

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.942

GnomAD2 exomes AF: 0.964 AC: 241384 AN: 250490 AF XY: 0.966

Gnomad AFR exome AF: 0.810

Gnomad AMR exome AF: 0.950

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 0.920

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.978

GnomAD4 exome AF: 0.985 AC: 1440157 AN: 1461400 Hom.: 710666 Cov.: 53 AF XY: 0.984 AC XY: 715553 AN XY: 726938

African (AFR) AF: 0.809 AC: 27066 AN: 33470

American (AMR) AF: 0.948 AC: 42365 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 25974 AN: 26126

East Asian (EAS) AF: 0.938 AC: 37220 AN: 39694

South Asian (SAS) AF: 0.923 AC: 79518 AN: 86138

European-Finnish (FIN) AF: 1.00 AC: 53345 AN: 53346

Middle Eastern (MID) AF: 0.972 AC: 5602 AN: 5764

European-Non Finnish (NFE) AF: 0.999 AC: 1110332 AN: 1111810

Other (OTH) AF: 0.973 AC: 58735 AN: 60384

GnomAD4 genome AF: 0.935 AC: 142338 AN: 152160 Hom.: 67098 Cov.: 30 AF XY: 0.935 AC XY: 69540 AN XY: 74388

African (AFR) AF: 0.814 AC: 33780 AN: 41484

American (AMR) AF: 0.932 AC: 14231 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3455 AN: 3472

East Asian (EAS) AF: 0.919 AC: 4731 AN: 5146

South Asian (SAS) AF: 0.921 AC: 4450 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67890 AN: 68028

Other (OTH) AF: 0.943 AC: 1988 AN: 2108

Alfa AF: 0.976 Hom.: 36769

Bravo AF: 0.926

Asia WGS AF: 0.900 AC: 3129 AN: 3478

EpiCase AF: 0.997

EpiControl AF: 0.998

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Amish lethal microcephaly (2)
-	-	1	Progressive demyelinating neuropathy with bilateral striatal necrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.12
DANN	Benign	0.27
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs7213318; hg19: chr17-73279624; COSMIC: COSV57467071; COSMIC: COSV57467071;