6-107705289-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198081.5(SCML4):c.1156G>T(p.Asp386Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCML4 NM_198081.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

Genes affected

SCML4 (HGNC:21397): (Scm polycomb group protein like 4) 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCML4	NM_198081.5	c.1156G>T	p.Asp386Tyr	missense_variant	8/8	ENST00000369020.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCML4	ENST00000369020.8	c.1156G>T	p.Asp386Tyr	missense_variant	8/8	5	NM_198081.5	P1
SCML4	ENST00000369025.6	c.430G>T	p.Asp144Tyr	missense_variant	4/4	1
SCML4	ENST00000369022.6	c.982G>T	p.Asp328Tyr	missense_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 08, 2023

The c.1156G>T (p.D386Y) alteration is located in exon 8 (coding exon 7) of the SCML4 gene. This alteration results from a G to T substitution at nucleotide position 1156, causing the aspartic acid (D) at amino acid position 386 to be replaced by a tyrosine (Y). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.78
MutPred		0.51		.;.;Loss of ubiquitination at K390 (P = 0.0435);
MVP		0.59
MPC		0.73
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-108026493;