2-216432810-G-T

Variant names:

• chr2-216432810-G-T
• NM_014140.4:c.1427G>T

Variant summary

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

The NM_014140.4(SMARCAL1):​c.1427G>T​(p.Arg476Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCAL1 NM_014140.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

Genes affected

SMARCAL1 (HGNC:11102): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1) The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. [provided by RefSeq, Jul 2008]

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, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCAL1	NM_014140.4	c.1427G>T	p.Arg476Leu	missense_variant	Exon 8 of 18	ENST00000357276.9	NP_054859.2
SMARCAL1	NM_001127207.2	c.1427G>T	p.Arg476Leu	missense_variant	Exon 8 of 18		NP_001120679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.1427G>T	p.Arg476Leu	missense_variant	Exon 8 of 18	2	NM_014140.4	ENSP00000349823.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;D
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.26	B;B;.
Vest4		0.72
MutPred		0.75		Gain of ubiquitination at K477 (P = 0.0751);Gain of ubiquitination at K477 (P = 0.0751);.;
MVP		0.95
MPC		0.87
ClinPred		0.95	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.54
gMVP		0.73

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: chr2-217297533;