rs35907255

Variant names:

• chr2-216415127-T-C
• rs35907255
• NM_014140.4:c.423T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014140.4(SMARCAL1):​c.423T>C​(p.Tyr141Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,408 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (138 hom.)
• Consequence: SMARCAL1 NM_014140.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0690
• Publications: 5 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: ClinGen, PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-216415127-T-C is Benign according to our data. Variant chr2-216415127-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.069 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0092 (1402/152348) while in subpopulation AMR AF = 0.015 (230/15304). AF 95% confidence interval is 0.0134. There are 9 homozygotes in GnomAd4. There are 657 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

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.423T>C	p.Tyr141Tyr	synonymous	Exon 3 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.423T>C	p.Tyr141Tyr	synonymous	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.423T>C	p.Tyr141Tyr	synonymous	Exon 3 of 18	ENSP00000349823.4	Q9NZC9
	SMARCAL1	ENST00000358207.9	TSL:1	c.423T>C	p.Tyr141Tyr	synonymous	Exon 3 of 18	ENSP00000350940.5	Q9NZC9
	SMARCAL1	ENST00000392128.6	TSL:1	c.15T>C	p.Tyr5Tyr	synonymous	Exon 1 of 15	ENSP00000375974.2	H7BYI2

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1402 AN: 152230 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00969 AC: 2435 AN: 251164 AF XY: 0.0106

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0117 AC: 17086 AN: 1461060 Hom.: 138 Cov.: 32 AF XY: 0.0118 AC XY: 8593 AN XY: 726790

African (AFR) AF: 0.00198 AC: 66 AN: 33364

American (AMR) AF: 0.00883 AC: 394 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 288 AN: 26118

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.0104 AC: 895 AN: 86240

European-Finnish (FIN) AF: 0.00479 AC: 256 AN: 53414

Middle Eastern (MID) AF: 0.0154 AC: 89 AN: 5768

European-Non Finnish (NFE) AF: 0.0129 AC: 14389 AN: 1111508

Other (OTH) AF: 0.0117 AC: 706 AN: 60348

GnomAD4 genome AF: 0.00920 AC: 1402 AN: 152348 Hom.: 9 Cov.: 33 AF XY: 0.00882 AC XY: 657 AN XY: 74492

African (AFR) AF: 0.00255 AC: 106 AN: 41588

American (AMR) AF: 0.0150 AC: 230 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4826

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 899 AN: 68030

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0115 Hom.: 23

Bravo AF: 0.00968

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0149

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Schimke immuno-osseous dysplasia (5)
-	-	3	not provided (3)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.70
PhyloP100		-0.069
PromoterAI		0.038	Neutral
Mutation Taster		=100/0	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: rs35907255; hg19: chr2-217279850;