rs139646526

Variant names:

• chr16-51141750-T-C
• rs139646526
• NM_002968.3:c.472A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-51141750-T-C
• chr16-51141750-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002968.3(SALL1):​c.472A>G​(p.Ser158Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,517,888 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: SALL1 NM_002968.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.491
• Publications: 5 publications found

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]

SALL1 Gene-Disease associations (from GenCC):

• Townes-Brocks syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Townes-Brocks syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003352046).
• BP6: Variant 16-51141750-T-C is Benign according to our data. Variant chr16-51141750-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00384 (581/151210) while in subpopulation AFR AF = 0.00883 (365/41322). AF 95% confidence interval is 0.00809. There are 5 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 581 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002968.3. 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
	SALL1	NM_002968.3	MANE Select	c.472A>G	p.Ser158Gly	missense	Exon 2 of 3	NP_002959.2
	SALL1	NM_001127892.2		c.181A>G	p.Ser61Gly	missense	Exon 2 of 3	NP_001121364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL1	ENST00000251020.9	TSL:1 MANE Select	c.472A>G	p.Ser158Gly	missense	Exon 2 of 3	ENSP00000251020.4
	SALL1	ENST00000566102.1	TSL:1	c.77-4198A>G		intron	N/A	ENSP00000455582.1
	SALL1	ENST00000440970.6	TSL:5	c.472A>G	p.Ser158Gly	missense	Exon 3 of 4	ENSP00000407914.2

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 582 AN: 151094 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00888

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00135 AC: 330 AN: 243684 AF XY: 0.00138

Gnomad AFR exome AF: 0.00730

Gnomad AMR exome AF: 0.000651

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00118

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00200 AC: 2733 AN: 1366678 Hom.: 6 Cov.: 43 AF XY: 0.00200 AC XY: 1360 AN XY: 679754

African (AFR) AF: 0.00874 AC: 281 AN: 32156

American (AMR) AF: 0.000747 AC: 32 AN: 42854

Ashkenazi Jewish (ASJ) AF: 0.0000401 AC: 1 AN: 24924

East Asian (EAS) AF: 0.000875 AC: 34 AN: 38868

South Asian (SAS) AF: 0.000756 AC: 63 AN: 83280

European-Finnish (FIN) AF: 0.000230 AC: 11 AN: 47780

Middle Eastern (MID) AF: 0.00110 AC: 6 AN: 5454

European-Non Finnish (NFE) AF: 0.00210 AC: 2175 AN: 1034716

Other (OTH) AF: 0.00229 AC: 130 AN: 56646

GnomAD4 genome AF: 0.00384 AC: 581 AN: 151210 Hom.: 5 Cov.: 32 AF XY: 0.00365 AC XY: 270 AN XY: 73920

African (AFR) AF: 0.00883 AC: 365 AN: 41322

American (AMR) AF: 0.00125 AC: 19 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10552

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

European-Non Finnish (NFE) AF: 0.00165 AC: 111 AN: 67370

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00477

ESP6500AA AF: 0.00344 AC: 15

ESP6500EA AF: 0.000702 AC: 6

ExAC AF: 0.00166 AC: 198

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 20, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SALL1: BP4, BS2

SALL1-related disorder Benign:1

Mar 23, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Townes syndrome Benign:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.57
DANN	Benign	0.089
DEOGEN2	Benign	0.17	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.49
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.040
Sift	Benign	0.16	T
Sift4G	Benign	0.45	T
Polyphen		0.0080	B
Vest4		0.10
MVP		0.35
MPC		0.18
ClinPred		0.0016	T
GERP RS		-0.45
Varity_R		0.039
gMVP		0.13
Mutation Taster		=92/8	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: rs139646526; hg19: chr16-51175661; COSMIC: COSV51755083; COSMIC: COSV51755083;