Genetic Variant NM_001145018.3:c.157C>G (chr11-119193865-G-C) – 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_001145018.3(DRC12):c.157C>G(p.Arg53Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,262 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DRC12
NM_001145018.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

Genes affected

DRC12 (HGNC:27446): (dynein regulatory complex subunit 12 homolog) Enables identical protein binding activity. [provided by Alliance of Genome Resources, Apr 2022]

DRC12 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=0.38253385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC12	NM_001145018.3 link	c.157C>G	p.Arg53Gly	missense_variant	Exon 4 of 7	ENST00000503566.7	NP_001138490.1	Q494R4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DRC12	ENST00000503566.7 link	c.157C>G	p.Arg53Gly	missense_variant	Exon 4 of 7	5	NM_001145018.3	ENSP00000423567.2	Q494R4-1
DRC12	ENST00000415318.2 link	c.157C>G	p.Arg53Gly	missense_variant	Exon 5 of 8	5		ENSP00000445431.1	Q494R4-1
DRC12	ENST00000375140.7 link	n.653C>G		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399262

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690146

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:

31598

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078948

Other (OTH)

AF:

0.00

AC:

AN:

57998

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.74

.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.38

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.9

M;M

PhyloP100

1.3

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.12

Sift

Benign

0.035

D;D

Sift4G

Benign

0.28

T;T

Polyphen

0.93

P;P

Vest4

0.48

MutPred

0.21

Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);

MVP

0.43

MPC

0.68

ClinPred

0.96

GERP RS

3.7

Varity_R

0.12

gMVP

0.25

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over