rs2271335

Variant names:

• chr2-216468028-G-A
• rs2271335
• NM_014140.4:c.2226G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-216468028-G-A
• chr2-216468028-G-C
• chr2-216468028-G-T

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.2226G>A​(p.Thr742Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000482 in 1,612,474 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T742T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: SMARCAL1 NM_014140.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.63
• Publications: 3 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-216468028-G-A is Benign according to our data. Variant chr2-216468028-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000302 (46/152296) while in subpopulation SAS AF = 0.00643 (31/4824). AF 95% confidence interval is 0.00465. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	NM_014140.4	MANE Select	c.2226G>A	p.Thr742Thr	synonymous	Exon 14 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.2226G>A	p.Thr742Thr	synonymous	Exon 14 of 18	NP_001120679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	ENST00000357276.9	TSL:2 MANE Select	c.2226G>A	p.Thr742Thr	synonymous	Exon 14 of 18	ENSP00000349823.4
	SMARCAL1	ENST00000358207.9	TSL:1	c.2226G>A	p.Thr742Thr	synonymous	Exon 14 of 18	ENSP00000350940.5
	SMARCAL1	ENST00000392128.6	TSL:1	c.1752G>A	p.Thr584Thr	synonymous	Exon 11 of 15	ENSP00000375974.2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00107 AC: 270 AN: 251360 AF XY: 0.00137

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000924

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000501 AC: 732 AN: 1460178 Hom.: 7 Cov.: 30 AF XY: 0.000699 AC XY: 508 AN XY: 726522

African (AFR) AF: 0.000120 AC: 4 AN: 33444

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00146 AC: 58 AN: 39690

South Asian (SAS) AF: 0.00724 AC: 624 AN: 86220

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53362

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110510

Other (OTH) AF: 0.000497 AC: 30 AN: 60334

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74474

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000740 Hom.: 0

Bravo AF: 0.000249

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Schimke immuno-osseous dysplasia (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.075
DANN	Benign	0.28
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2271335; hg19: chr2-217332751; COSMIC: COSV61920188;