Genetic Variant NM_080650.4:c.122G>C (chr15-35538464-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_080650.4(DPH6):c.122G>C(p.Gly41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,512,592 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. G41E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00075 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

DPH6
NM_080650.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0130

Publications

4 publications found

Variant links:

Genes affected

DPH6 (HGNC:30543): (diphthamine biosynthesis 6) Enables diphthine-ammonia ligase activity. Predicted to be involved in peptidyl-diphthamide biosynthetic process from peptidyl-histidine. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DPH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005464107).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080650.4. 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
	DPH6	NM_080650.4	MANE Select	c.122G>C	p.Gly41Ala	missense	Exon 3 of 9	NP_542381.1	Q7L8W6-1
	DPH6	NM_001141972.2		c.122G>C	p.Gly41Ala	missense	Exon 3 of 4	NP_001135444.1	Q7L8W6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPH6	ENST00000256538.9	TSL:1 MANE Select	c.122G>C	p.Gly41Ala	missense	Exon 3 of 9	ENSP00000256538.4	Q7L8W6-1
DPH6	ENST00000440392.3	TSL:1	c.122G>C	p.Gly41Ala	missense	Exon 3 of 4	ENSP00000406976.2	Q7L8W6-2
DPH6	ENST00000896513.1		c.122G>C	p.Gly41Ala	missense	Exon 3 of 9	ENSP00000566572.1

Frequencies

GnomAD3 genomes

AF:

0.000750

AC:

114

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00715

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:

0.000480

GnomAD2 exomes

AF:

0.00118

AC:

270

AN:

228604

AF XY:

0.000954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00920

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000367

GnomAD4 exome

AF:

0.000270

AC:

368

AN:

1360486

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

164

AN XY:

667608

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31524

American (AMR)

AF:

0.00894

AC:

349

AN:

39038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23494

East Asian (EAS)

AF:

0.00

AC:

AN:

37896

South Asian (SAS)

AF:

0.00

AC:

AN:

71314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5378

European-Non Finnish (NFE)

AF:

9.55e-7

AC:

AN:

1046770

Other (OTH)

AF:

0.000308

AC:

AN:

55182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000749

AC:

114

AN:

152106

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41496

American (AMR)

AF:

0.00714

AC:

109

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000296

Hom.:

Bravo

AF:

0.00112

ExAC

AF:

0.000833

AC:

101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0026

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.69

M_CAP

Benign

0.0061

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.99

PhyloP100

-0.013

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.94

REVEL

Benign

0.012

Sift

Benign

0.25

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.12

MutPred

0.38

Gain of helix (P = 0.132)

MVP

0.14

MPC

0.19

ClinPred

0.0062

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.33

Mutation Taster

=98/2

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over