5-110738249-T-C

Variant names:

• chr5-110738249-T-C
• rs147877745
• NM_001303250.3:c.10+2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PVS1 BS1_Supporting

The NM_001303250.3(SLC25A46):​c.10+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,286,456 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (1 hom.)
• Consequence: SLC25A46 NM_001303250.3 splice_donor, intron
• Scores: Splicing: ADA: 0.5943
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 1.39
• Publications: 0 publications found

Genes affected

SLC25A46 (HGNC:25198): (solute carrier family 25 member 46) This gene encodes a mitochondrial solute carrier protein family member. It functions in promoting mitochondrial fission, and prevents the formation of hyperfilamentous mitochondria. Mutation of this gene results in neuropathy and optic atrophy. [provided by RefSeq, Aug 2016]

TMEM232 (HGNC:37270): (transmembrane protein 232) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000539 (82/152046) while in subpopulation NFE AF = 0.000794 (54/67976). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_001303250.3	c.10+2T>C		splice_donor_variant, intron_variant	Intron 1 of 7		NP_001290179.1
TMEM232	XM_006714670.4	c.-298+473A>G		intron_variant	Intron 1 of 15		XP_006714733.1
TMEM232	XM_011543552.3	c.-649+473A>G		intron_variant	Intron 1 of 16		XP_011541854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000513807.5	c.-204+2T>C		splice_donor_variant, intron_variant	Intron 1 of 7	2		ENSP00000421134.1
TMEM232	ENST00000515278.6	c.-298+473A>G		intron_variant	Intron 1 of 6	5		ENSP00000421614.2
TMEM232	ENST00000503527.6	n.197+473A>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000540 AC: 82 AN: 151928 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000403 AC: 51 AN: 126476 AF XY: 0.000346

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.0000421

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000892

Gnomad OTH exome AF: 0.000256

GnomAD4 exome AF: 0.000980 AC: 1112 AN: 1134410 Hom.: 1 Cov.: 29 AF XY: 0.000927 AC XY: 516 AN XY: 556450

African (AFR) AF: 0.000989 AC: 24 AN: 24276

American (AMR) AF: 0.00 AC: 0 AN: 28052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15896

East Asian (EAS) AF: 0.00 AC: 0 AN: 12670

South Asian (SAS) AF: 0.00 AC: 0 AN: 75900

European-Finnish (FIN) AF: 0.000318 AC: 4 AN: 12596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4004

European-Non Finnish (NFE) AF: 0.00115 AC: 1057 AN: 919668

Other (OTH) AF: 0.000653 AC: 27 AN: 41348

GnomAD4 genome AF: 0.000539 AC: 82 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74322

African (AFR) AF: 0.000651 AC: 27 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

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Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
PhyloP100		1.4
PromoterAI		0.047	Neutral
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Pathogenic	0.76

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147877745; hg19: chr5-110073950;