rs74499562

chr16-51137215-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002968.3(SALL1):c.3872A>G(p.Asn1291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,114 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 31)
  • Exomes 𝑓: 0.013 (150 hom.)
• Consequence: SALL1 NM_002968.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.426

Genes affected

SALL1 (HGNC:10524): (spalt like transcription factor 1) The protein encoded by this gene is a zinc finger transcriptional repressor and may be part of the NuRD histone deacetylase complex (HDAC). Defects in this gene are a cause of Townes-Brocks syndrome (TBS) as well as bronchio-oto-renal syndrome (BOR). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030624866).
• BP6: Variant 16-51137215-T-C is Benign according to our data. Variant chr16-51137215-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 218510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-51137215-T-C is described in Lovd as [Benign]. Variant chr16-51137215-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1552/152236) while in subpopulation NFE AF= 0.0164 (1117/68008). AF 95% confidence interval is 0.0156. There are 14 homozygotes in gnomad4. There are 714 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1554 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL1	NM_002968.3	c.3872A>G	p.Asn1291Ser	missense_variant	3/3	ENST00000251020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL1	ENST00000251020.9	c.3872A>G	p.Asn1291Ser	missense_variant	3/3	1	NM_002968.3	P2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 152118 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00707

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.00960

GnomAD3 exomes AF: 0.0103 AC: 2583 AN: 251466 Hom.: 22 AF XY: 0.0108 AC XY: 1474 AN XY: 135912

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00774

Gnomad FIN exome AF: 0.00892

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0130 AC: 19051 AN: 1461878 Hom.: 150 Cov.: 30 AF XY: 0.0130 AC XY: 9478 AN XY: 727236

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00765

Gnomad4 FIN exome AF: 0.00848

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0102 AC: 1552 AN: 152236 Hom.: 14 Cov.: 31 AF XY: 0.00959 AC XY: 714 AN XY: 74454

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00666

Gnomad4 FIN AF: 0.00772

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.00950

Alfa AF: 0.0129 Hom.: 4

Bravo AF: 0.00968

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0100 AC: 1220

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 02, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Dec 31, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Townes-Brocks syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Townes syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0020
Dann	Benign	0.42
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	D;N;N;N
PROVEAN	Benign	0.66	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0	.;B
Vest4		0.070
MPC		0.16
ClinPred		0.0018	T
GERP RS		-2.4
Varity_R		0.024
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs74499562; hg19: chr16-51171126;