Genetic Variant NM_145267.3:c.5C>A (chr6-70566945-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145267.3(SDHAF4):c.5C>A(p.Thr2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SDHAF4
NM_145267.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.345

Publications

0 publications found

Variant links:

Genes affected

SDHAF4 (HGNC:20957): (succinate dehydrogenase complex assembly factor 4) Predicted to enable enzyme activator activity. Involved in cellular respiration and mitochondrial respiratory chain complex II assembly. Predicted to be located in mitochondrial matrix. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SDHAF4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06980243).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145267.3. 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
	SDHAF4	NM_145267.3	MANE Select	c.5C>A	p.Thr2Asn	missense	Exon 1 of 3	NP_660310.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF4	ENST00000370474.4	TSL:1 MANE Select	c.5C>A	p.Thr2Asn	missense	Exon 1 of 3	ENSP00000359505.3	Q5VUM1
	SDHAF4	ENST00000468640.1	TSL:3	n.29C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1432926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709858

African (AFR)

AF:

0.00

AC:

AN:

32882

American (AMR)

AF:

0.00

AC:

AN:

40520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25554

East Asian (EAS)

AF:

0.00

AC:

AN:

38266

South Asian (SAS)

AF:

0.00

AC:

AN:

81788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097784

Other (OTH)

AF:

0.00

AC:

AN:

59258

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

6501

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.9

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0091

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.24

M_CAP

Benign

0.0047

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.99

PhyloP100

-0.34

PROVEAN

Benign

-0.18

REVEL

Benign

0.031

Sift

Benign

0.30

Sift4G

Benign

0.069

Polyphen

0.099

Vest4

0.18

MutPred

0.19

Loss of phosphorylation at T2 (P = 0.0118)

MVP

0.061

MPC

0.11

ClinPred

0.18

GERP RS

2.8

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.071

gMVP

0.18

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over