rs766116322

Variant names:

• chr5-110755521-C-A
• rs766116322
• NM_138773.4:c.620C>A
• SLC25A46 p.Ser207Tyr

Your query was ambiguous. Multiple possible variants found:

• chr5-110755521-C-A
• chr5-110755521-C-G
• chr5-110755521-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138773.4(SLC25A46):​c.620C>A​(p.Ser207Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000283 in 1,413,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense, splice_region
• Scores: Splicing: ADA: 0.1814
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90
• Publications: 1 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]

SLC25A46 Gene-Disease associations (from GenCC):

• neuropathy, hereditary motor and sensory, type 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• pontocerebellar hypoplasia, type 1E

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary motor and sensory neuropathy type 6

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138773.4. 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
	SLC25A46	NM_138773.4	MANE Select	c.620C>A	p.Ser207Tyr	missense splice_region	Exon 6 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.620C>A	p.Ser207Tyr	missense splice_region	Exon 6 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.347C>A	p.Ser116Tyr	missense splice_region	Exon 6 of 8	NP_001290179.1	B4DY98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A46	ENST00000355943.8	TSL:1 MANE Select	c.620C>A	p.Ser207Tyr	missense splice_region	Exon 6 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.620C>A	p.Ser207Tyr	missense splice_region	Exon 6 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.620C>A	p.Ser207Tyr	missense splice_region	Exon 6 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1413250 Hom.: 0 Cov.: 25 AF XY: 0.00000284 AC XY: 2 AN XY: 703292

African (AFR) AF: 0.00 AC: 0 AN: 30904

American (AMR) AF: 0.00 AC: 0 AN: 36744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24848

East Asian (EAS) AF: 0.00 AC: 0 AN: 38460

South Asian (SAS) AF: 0.00 AC: 0 AN: 78274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1087180

Other (OTH) AF: 0.00 AC: 0 AN: 58416

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuropathy, hereditary motor and sensory, type 6B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.55
Sift	Benign	0.032	D
Sift4G	Benign	0.070	T
PromoterAI		-0.034	Neutral
Varity_R		0.19
gMVP		0.79
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.37
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766116322;

hg19: chr5-110091221;