rs139646526

Positions:

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

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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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:5
• Conservation: PhyloP100: 0.491

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=0.003352046).
• BP6: Variant 16-51141750-T-C is Benign according to our data. Variant chr16-51141750-T-C is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 581 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL1	NM_002968.3	c.472A>G	p.Ser158Gly	missense_variant	2/3	ENST00000251020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL1	ENST00000251020.9	c.472A>G	p.Ser158Gly	missense_variant	2/3	1	NM_002968.3	P2

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

GnomAD3 exomes AF: 0.00135 AC: 330 AN: 243684 Hom.: 0 AF XY: 0.00138 AC XY: 183 AN XY: 132414

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 SAS exome AF: 0.000600

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

Gnomad4 AFR exome AF: 0.00874

Gnomad4 AMR exome AF: 0.000747

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.000875

Gnomad4 SAS exome AF: 0.000756

Gnomad4 FIN exome AF: 0.000230

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00229

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

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.00237

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2017	- -

SALL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2021

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

SALL1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.34	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.45	T;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

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: rs139646526; hg19: chr16-51175661; COSMIC: COSV51755083; COSMIC: COSV51755083;