X-17746051-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001037540.3(SCML1):c.151A>G(p.Thr51Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,074,361 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000034 (0 hom. 15 hem.)
• Consequence: SCML1 NM_001037540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.729

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04171139).
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCML1	NM_001037540.3	c.151A>G	p.Thr51Ala	missense_variant	4/8	ENST00000380041.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCML1	ENST00000380041.8	c.151A>G	p.Thr51Ala	missense_variant	4/8	5	NM_001037540.3	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000229 AC: 4 AN: 174516 Hom.: 0 AF XY: 0.0000335 AC XY: 2 AN XY: 59670

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000505

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 36 AN: 1074361 Hom.: 0 Cov.: 23 AF XY: 0.0000438 AC XY: 15 AN XY: 342553

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000424

Gnomad4 OTH exome AF: 0.0000222

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.151A>G (p.T51A) alteration is located in exon 4 (coding exon 3) of the SCML1 gene. This alteration results from a A to G substitution at nucleotide position 151, causing the threonine (T) at amino acid position 51 to be replaced by an alanine (A). 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	0.081
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	5.1
Dann	Benign	0.75
DEOGEN2	Benign	0.017	T;.;.
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.41	T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Benign	0.075
Sift	Uncertain	0.012	D;D;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.96	P;D;.
Vest4		0.084
MVP		0.21
MPC		0.96
ClinPred		0.16	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.055

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs184140147; hg19: chrX-17764171; COSMIC: COSV66241088;