NM_001037540.3:c.281C>G

Variant names:

• chrX-17749482-C-G
• rs142861368
• NM_001037540.3:c.281C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001037540.3(SCML1):​c.281C>G​(p.Ala94Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000947 in 1,055,800 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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. A94V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: SCML1 NM_001037540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.39
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10529405).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCML1	NM_001037540.3	MANE Select	c.281C>G	p.Ala94Gly	missense	Exon 5 of 8	NP_001032629.1	Q9UN30-3
	SCML1	NM_006746.6		c.200C>G	p.Ala67Gly	missense	Exon 4 of 7	NP_006737.2	Q9UN30-2
	SCML1	NM_001037535.3		c.-83C>G		5_prime_UTR	Exon 3 of 6	NP_001032624.1	Q9UN30-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCML1	ENST00000380041.8	TSL:5 MANE Select	c.281C>G	p.Ala94Gly	missense	Exon 5 of 8	ENSP00000369380.3	Q9UN30-3
	SCML1	ENST00000380043.7	TSL:1	c.200C>G	p.Ala67Gly	missense	Exon 4 of 7	ENSP00000369382.3	Q9UN30-2
	SCML1	ENST00000380045.7	TSL:1	c.-83C>G		5_prime_UTR	Exon 3 of 6	ENSP00000369384.3	Q9UN30-1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000576 AC: 1 AN: 173701 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000402

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: 0.00

GnomAD4 exome AF: 9.47e-7 AC: 1 AN: 1055800 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 326398

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25419

American (AMR) AF: 0.0000299 AC: 1 AN: 33401

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18893

East Asian (EAS) AF: 0.00 AC: 0 AN: 29969

South Asian (SAS) AF: 0.00 AC: 0 AN: 51299

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3990

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 807847

Other (OTH) AF: 0.00 AC: 0 AN: 44576

⚠️ 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.

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0010
DANN	Benign	0.85
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.075
Sift	Uncertain	0.013	D
Sift4G	Benign	0.15	T
Polyphen		0.92	P
Vest4		0.13
MutPred		0.33		Loss of helix (P = 0.0033)
MVP		0.12
MPC		1.0
ClinPred		0.14	T
GERP RS		-4.2
Varity_R		0.076
gMVP		0.038
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs142861368; hg19: chrX-17767602;