NM_014140.4:c.29G>T

Variant names:

• chr2-216414733-G-T
• rs775840273
• NM_014140.4:c.29G>T

Variant summary

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

The NM_014140.4(SMARCAL1):​c.29G>T​(p.Arg10Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: SMARCAL1 NM_014140.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89
• Publications: 0 publications found

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]

SMARCAL1 Gene-Disease associations (from GenCC):

• Schimke immuno-osseous dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

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=0.21697766).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014140.4. 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
	SMARCAL1	NM_014140.4	MANE Select	c.29G>T	p.Arg10Met	missense	Exon 3 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.29G>T	p.Arg10Met	missense	Exon 3 of 18	NP_001120679.1	Q9NZC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	ENST00000357276.9	TSL:2 MANE Select	c.29G>T	p.Arg10Met	missense	Exon 3 of 18	ENSP00000349823.4	Q9NZC9
	SMARCAL1	ENST00000358207.9	TSL:1	c.29G>T	p.Arg10Met	missense	Exon 3 of 18	ENSP00000350940.5	Q9NZC9
	SMARCAL1	ENST00000932386.1		c.29G>T	p.Arg10Met	missense	Exon 3 of 19	ENSP00000602445.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250914 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.00

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 Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.0000482 AC: 2 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68054

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Schimke immuno-osseous dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.95	P
Vest4		0.46
MutPred		0.12		Loss of methylation at K11 (P = 0.0267)
MVP		0.97
MPC		0.72
ClinPred		0.91	D
GERP RS		2.5
PromoterAI		0.064	Neutral
Varity_R		0.082
gMVP		0.26
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs775840273; hg19: chr2-217279456;