Genetic Variant NM_001037540.3:c.281C>T (chrX-17749482-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001037540.3(SCML1):c.281C>T(p.Ala94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,167,932 control chromosomes in the GnomAD database, including 8 homozygotes. There are 392 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A94A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., 78 hem., cov: 24)

Exomes 𝑓: 0.0011 ( 6 hom. 314 hem. )

Consequence

SCML1
NM_001037540.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.39

Publications

3 publications found

Variant links:

Genes affected

SCML1 (HGNC:10580): (Scm polycomb group protein like 1) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in negative regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SCML1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050575435).

BP6

Variant X-17749482-C-T is Benign according to our data. Variant chrX-17749482-C-T is described in ClinVar as Benign. ClinVar VariationId is 720065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00111 (1170/1055775) while in subpopulation AMR AF = 0.0199 (666/33391). AF 95% confidence interval is 0.0187. There are 6 homozygotes in GnomAdExome4. There are 314 alleles in the male GnomAdExome4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCML1	NM_001037540.3	MANE Select	c.281C>T	p.Ala94Val	missense	Exon 5 of 8	NP_001032629.1	Q9UN30-3
SCML1	NM_006746.6		c.200C>T	p.Ala67Val	missense	Exon 4 of 7	NP_006737.2	Q9UN30-2
SCML1	NM_001037535.3		c.-83C>T		5_prime_UTR	Exon 3 of 6	NP_001032624.1	Q9UN30-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCML1	ENST00000380041.8	TSL:5 MANE Select	c.281C>T	p.Ala94Val	missense	Exon 5 of 8	ENSP00000369380.3	Q9UN30-3
SCML1	ENST00000380043.7	TSL:1	c.200C>T	p.Ala67Val	missense	Exon 4 of 7	ENSP00000369382.3	Q9UN30-2
SCML1	ENST00000380045.7	TSL:1	c.-83C>T		5_prime_UTR	Exon 3 of 6	ENSP00000369384.3	Q9UN30-1

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

238

AN:

112106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000812

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00829

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00149

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00265

GnomAD2 exomes

AF:

0.00380

AC:

660

AN:

173701

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.000464

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00919

Gnomad FIN exome

AF:

0.00133

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.00353

GnomAD4 exome

AF:

0.00111

AC:

1170

AN:

1055775

Hom.:

Cov.:

AF XY:

0.000962

AC XY:

314

AN XY:

326393

show subpopulations

African (AFR)

AF:

0.000551

AC:

AN:

25419

American (AMR)

AF:

0.0199

AC:

666

AN:

33391

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18893

East Asian (EAS)

AF:

0.0101

AC:

304

AN:

29965

South Asian (SAS)

AF:

0.0000390

AC:

AN:

51298

European-Finnish (FIN)

AF:

0.00191

AC:

AN:

40406

Middle Eastern (MID)

AF:

0.000752

AC:

AN:

3990

European-Non Finnish (NFE)

AF:

0.0000421

AC:

AN:

807840

Other (OTH)

AF:

0.00157

AC:

AN:

44573

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00214

AC:

240

AN:

112157

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

AN XY:

34353

show subpopulations

African (AFR)

AF:

0.000811

AC:

AN:

30842

American (AMR)

AF:

0.0158

AC:

167

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00804

AC:

AN:

3609

South Asian (SAS)

AF:

0.00

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00149

AC:

AN:

6056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53269

Other (OTH)

AF:

0.00262

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000829

Hom.:

Bravo

AF:

0.00311

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.00288

AC:

350

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0010

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.012

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

PhyloP100

-2.4

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.37

REVEL

Benign

0.017

Sift

Benign

0.22

Sift4G

Benign

0.40

Polyphen

0.31

Vest4

0.060

MVP

0.12

MPC

0.93

ClinPred

0.0050

GERP RS

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.031

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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