rs146454164

chr16-51140318-G-A

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.1904C>T(p.Pro635Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00304 in 1,614,090 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 (i.e. P635S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (27 hom.)
• Consequence: SALL1 NM_002968.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.57

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=0.0043956935).
• BP6: Variant 16-51140318-G-A is Benign according to our data. Variant chr16-51140318-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-51140318-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00282 (429/152318) while in subpopulation NFE AF= 0.00375 (255/68030). AF 95% confidence interval is 0.00337. There are 1 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL1	NM_002968.3	c.1904C>T	p.Pro635Leu	missense_variant	2/3	ENST00000251020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL1	ENST00000251020.9	c.1904C>T	p.Pro635Leu	missense_variant	2/3	1	NM_002968.3	P2

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00324 AC: 812 AN: 250604 Hom.: 5 AF XY: 0.00307 AC XY: 416 AN XY: 135584

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00306 AC: 4478 AN: 1461772 Hom.: 27 Cov.: 53 AF XY: 0.00310 AC XY: 2251 AN XY: 727192

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0116

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.00283

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74476

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00358 Hom.: 1

Bravo AF: 0.00190

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00336 AC: 408

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SALL1: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 10, 2020

- -

SALL1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2022

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 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	14
Dann	Benign	0.87
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.75	D;D;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.037	D;D;D
Sift4G	Benign	0.13	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.045
MVP		0.18
MPC		0.22
ClinPred		0.015	T
GERP RS		1.8
Varity_R		0.031
gMVP		0.22

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: rs146454164; hg19: chr16-51174229; COSMIC: COSV51754039; COSMIC: COSV51754039;