Genetic Variant SMKR1:p.Tyr36Cys (chr7-129512350-A-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_001195243.2(SMKR1):c.107A>G(p.Tyr36Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000624 in 1,536,112 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 3 hom. )

Consequence

SMKR1
NM_001195243.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.68

Publications

4 publications found

Variant links:

Genes affected

SMKR1 (HGNC:43561): (small lysine rich protein 1)

SMKR1 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=0.05342403).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMKR1	NM_001195243.2 link	c.107A>G	p.Tyr36Cys	missense_variant	Exon 2 of 2	ENST00000462322.3	NP_001182172.1	H3BMG3
SMKR1	XM_024446620.2 link	c.164A>G	p.Tyr55Cys	missense_variant	Exon 2 of 2		XP_024302388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMKR1	ENST00000462322.3 link	c.107A>G	p.Tyr36Cys	missense_variant	Exon 2 of 2	1	NM_001195243.2	ENSP00000454370.1		H3BMG3
SMKR1	ENST00000488846.1 link	n.136A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000892

AC:

120

AN:

134592

AF XY:

0.000819

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.000737

Gnomad ASJ exome

AF:

0.000844

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.00338

GnomAD4 exome

AF:

0.000629

AC:

871

AN:

1383782

Hom.:

Cov.:

AF XY:

0.000640

AC XY:

437

AN XY:

682834

show subpopulations

African (AFR)

AF:

0.0000950

AC:

AN:

31590

American (AMR)

AF:

0.000672

AC:

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.000635

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35724

South Asian (SAS)

AF:

0.000909

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.0000885

AC:

AN:

33898

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000582

AC:

628

AN:

1078864

Other (OTH)

AF:

0.000846

AC:

AN:

57902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000571

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41566

American (AMR)

AF:

0.000589

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000852

AC:

AN:

68036

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00105

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00120

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.107A>G (p.Y36C) alteration is located in exon 2 (coding exon 2) of the SMKR1 gene. This alteration results from a A to G substitution at nucleotide position 107, causing the tyrosine (Y) at amino acid position 36 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.39

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.66

M_CAP

Benign

0.032

MetaRNN

Benign

0.053

PhyloP100

5.7

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-8.5

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Vest4

0.38

MVP

0.40

GERP RS

4.5

Varity_R

0.40

gMVP

0.61

Mutation Taster

=88/12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over