Genetic Variant NM_006713.4:c.31A>G (chr5-32588543-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006713.4(SUB1):c.31A>G(p.Ser11Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SUB1
NM_006713.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.08

Publications

2 publications found

Variant links:

Genes affected

SUB1 (HGNC:19985): (SUB1 regulator of transcription) Enables identical protein binding activity; single-stranded DNA binding activity; and transcription coactivator activity. Involved in negative regulation of DNA metabolic process and regulation of transcription by RNA polymerase II. Located in nucleolus and nucleoplasm. Part of transcription regulator complex. [provided by Alliance of Genome Resources, Apr 2022]

SUB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33599216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUB1	NM_006713.4 link	c.31A>G	p.Ser11Gly	missense_variant	Exon 2 of 5	ENST00000265073.9	NP_006704.3	P53999Q6IBA2
SUB1	XM_011513944.4 link	c.31A>G	p.Ser11Gly	missense_variant	Exon 3 of 6		XP_011512246.1	P53999Q6IBA2
SUB1	XM_047416661.1 link	c.31A>G	p.Ser11Gly	missense_variant	Exon 3 of 6		XP_047272617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUB1	ENST00000265073.9 link	c.31A>G	p.Ser11Gly	missense_variant	Exon 2 of 5	1	NM_006713.4	ENSP00000265073.4		P53999

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726760

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111542

Other (OTH)

AF:

0.0000166

AC:

AN:

60322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

T;T;T;T;T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

.;.;.;.;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.34

T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.9

L;L;L;L;L;.

PhyloP100

6.1

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.057

T;T;T;T;T;D

Sift4G

Uncertain

0.033

D;D;D;D;D;D

Polyphen

0.92

P;P;P;P;P;.

Vest4

0.36

MutPred

0.099

Loss of phosphorylation at S11 (P = 5e-04);Loss of phosphorylation at S11 (P = 5e-04);Loss of phosphorylation at S11 (P = 5e-04);Loss of phosphorylation at S11 (P = 5e-04);Loss of phosphorylation at S11 (P = 5e-04);Loss of phosphorylation at S11 (P = 5e-04);

MVP

0.55

MPC

0.068

ClinPred

0.77

GERP RS

5.7

Varity_R

0.17

gMVP

0.20

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over