Genetic Variant NM_016080.4:c.404C>T (chr17-775777-G-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_016080.4(GLOD4):c.404C>T(p.Ser135Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000031 in 1,613,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GLOD4
NM_016080.4 missense, splice_region

Scores

Splicing: ADA: 0.04905

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.00

Publications

0 publications found

Variant links:

Genes affected

GLOD4 (HGNC:14111): (glyoxalase domain containing 4) Enables cadherin binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

GLOD4 links:

Genome browser will be placed here

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=0.2388528).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLOD4	NM_016080.4	MANE Select	c.404C>T	p.Ser135Leu	missense splice_region	Exon 4 of 9	NP_057164.3
GLOD4	NM_001389725.1		c.602C>T	p.Ser201Leu	missense splice_region	Exon 5 of 10	NP_001376654.1
GLOD4	NM_001389726.1		c.515C>T	p.Ser172Leu	missense splice_region	Exon 5 of 10	NP_001376655.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLOD4	ENST00000301329.11	TSL:1 MANE Select	c.404C>T	p.Ser135Leu	missense splice_region	Exon 4 of 9	ENSP00000301329.6	Q9HC38-2
GLOD4	ENST00000301328.9	TSL:1	c.449C>T	p.Ser150Leu	missense splice_region	Exon 5 of 10	ENSP00000301328.5	Q9HC38-1
GLOD4	ENST00000891260.1		c.515C>T	p.Ser172Leu	missense splice_region	Exon 5 of 10	ENSP00000561319.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251356

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461058

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111338

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

M_CAP

Benign

0.045

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.99

PhyloP100

5.0

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.090

Sift

Benign

0.079

Sift4G

Benign

0.16

Polyphen

0.12

Vest4

0.35

MutPred

0.46

Loss of disorder (P = 0.0054)

MVP

0.75

MPC

0.12

ClinPred

0.42

GERP RS

4.7

Varity_R

0.11

gMVP

0.22

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.049

dbscSNV1_RF

Benign

0.27

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over