rs864621971

chr16-51141273-G-Achr16-51141273-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5 BP4 BS1_Supporting

The NM_002968.3(SALL1):c.949C>T(p.Pro317Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SALL1 NM_002968.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.72

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 Likely_benign. Variant got -1 ACMG points.

• PP5: Variant 16-51141273-G-A is Pathogenic according to our data. Variant chr16-51141273-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208167.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26929903).. Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000616 (9/1461820) while in subpopulation AMR AF= 0.0000894 (4/44724). AF 95% confidence interval is 0.0000298. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 53. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL1	NM_002968.3	c.949C>T	p.Pro317Ser	missense_variant	2/3	ENST00000251020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL1	ENST00000251020.9	c.949C>T	p.Pro317Ser	missense_variant	2/3	1	NM_002968.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461820 Hom.: 0 Cov.: 53 AF XY: 0.00000413 AC XY: 3 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Townes-Brocks syndrome 1 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	research	Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília	Apr 01, 2015	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 26380986) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.14	T;T;.
Polyphen		0.78	.;P;.
Vest4		0.41
MutPred		0.26		.;Loss of catalytic residue at P317 (P = 7e-04);.;
MVP		0.26
MPC		0.61
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.17
gMVP		0.37

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: rs864621971; hg19: chr16-51175184;