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GeneBe

16-51137197-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_002968.3(SALL1):c.3890T>G(p.Leu1297Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000395 in 152026 control chromosomes in the gnomAD Genomes database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 1 hom., cov: 31)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

SALL1
NM_002968.3 missense

Scores

6
7
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.55

Links

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1
?
Variant frequency is greater than expected. gnomad allele frequency = 0.0000395 (6/152026) while in subpopulation NFE AF= 0.0000882 (6/68018). AF 95% confidence interval is 0.0000376. There are 1 homozygotes in gnomad. There are 2 alleles in male gnomad subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SALL1NM_002968.3 linkuse as main transcriptc.3890T>G p.Leu1297Arg missense_variant 3/3 ENST00000251020.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SALL1ENST00000251020.9 linkuse as main transcriptc.3890T>G p.Leu1297Arg missense_variant 3/31 NM_002968.3 P2Q9NSC2-1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152026
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251472
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135916
show subpopulations
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:
0.0000527
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461886
Hom.:
0
AF XY:
0.0000234
AC XY:
17
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000331
Bravo
AF:
0.0000340
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

SALL1-related condition Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, Part of Exact SciencesSep 20, 2023The SALL1 c.3890T>G variant is predicted to result in the amino acid substitution p.Leu1297Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of European (non-Finnish) descent in gnomAD, including 1 homozygous individual (http://gnomad.broadinstitute.org/variant/16-51171108-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 08, 2022The c.3890T>G (p.L1297R) alteration is located in exon 3 (coding exon 3) of the SALL1 gene. This alteration results from a T to G substitution at nucleotide position 3890, causing the leucine (L) at amino acid position 1297 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Townes syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeFeb 08, 2022This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1297 of the SALL1 protein (p.Leu1297Arg). This variant is present in population databases (rs767612617, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SALL1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.18
Cadd
Pathogenic
28
Dann
Uncertain
1.0
Eigen
Pathogenic
0.68
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.065
D
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Benign
-0.55
T
MutationTaster
Benign
1.0
D;D;D;D
PROVEAN
Uncertain
-3.4
D;D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
.;D
Vest4
0.62
MutPred
0.36
.;Gain of solvent accessibility (P = 0.1071);
MVP
0.43
MPC
0.90
ClinPred
0.72
D
GERP RS
5.8
Varity_R
0.84
gMVP
0.79

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767612617; hg19: chr16-51171108; API