rs1295016936

Variant names:

• chr5-110739138-G-A
• rs1295016936
• NM_138773.4:c.19G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_138773.4(SLC25A46):​c.19G>A​(p.Asp7Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000043 in 1,396,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.17
• 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_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3762316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.19G>A	p.Asp7Asn	missense_variant	Exon 1 of 8	ENST00000355943.8	NP_620128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.19G>A	p.Asp7Asn	missense_variant	Exon 1 of 8	1	NM_138773.4	ENSP00000348211.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000132 AC: 2 AN: 151292 AF XY: 0.0000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1396290 Hom.: 0 Cov.: 31 AF XY: 0.00000436 AC XY: 3 AN XY: 688740

African (AFR) AF: 0.00 AC: 0 AN: 31542

American (AMR) AF: 0.0000280 AC: 1 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35716

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4940

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078716

Other (OTH) AF: 0.00 AC: 0 AN: 57884

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary motor and sensory, type 6B Uncertain:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1478064). This variant has not been reported in the literature in individuals affected with SLC25A46-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 7 of the SLC25A46 protein (p.Asp7Asn). -

Inborn genetic diseases Uncertain:1

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19G>A (p.D7N) alteration is located in exon 1 (coding exon 1) of the SLC25A46 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the aspartic acid (D) at amino acid position 7 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	2.0	M;M
PhyloP100		8.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.47	P;.
Vest4		0.25
MutPred		0.15		Gain of methylation at R4 (P = 0.1109);Gain of methylation at R4 (P = 0.1109);
MVP		0.82
MPC		0.099
ClinPred		0.87	D
GERP RS		4.9
PromoterAI		0.029	Neutral
Varity_R		0.26
gMVP		0.45
Mutation Taster		=36/64	disease causing

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: rs1295016936; hg19: chr5-110074839;