chr1-15935970-A-G

Position:

chr1-15935970-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_015001.3(SPEN):c.9730A>G(p.Thr3244Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000567 in 758,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (i.e. T3244P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.451

Variant links:

Genes affected

SPEN (HGNC:17575): (spen family transcriptional repressor) This gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors. [provided by RefSeq, Jul 2008]

SPEN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPEN. . Gene score misZ 2.8932 (greater than the threshold 3.09). Trascript score misZ 5.0985 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, Radio-Tartaglia syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.023690045).

BP6

Variant 1-15935970-A-G is Benign according to our data. Variant chr1-15935970-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3168965.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000605 (42/693710) while in subpopulation NFE AF= 0.0000771 (39/506080). AF 95% confidence interval is 0.0000577. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEN	NM_015001.3 linkuse as main transcript	c.9730A>G	p.Thr3244Ala	missense_variant	11/15	ENST00000375759.8	NP_055816.2	Q96T58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SPEN	ENST00000375759.8 linkuse as main transcript	c.9730A>G	p.Thr3244Ala	missense_variant	11/15	1	NM_015001.3	ENSP00000364912.3	Q96T58
SPEN	ENST00000704274.1 linkuse as main transcript	c.5326A>G	p.Thr1776Ala	missense_variant	1/4			ENSP00000515812.1	A0A994J7B7
SPEN	ENST00000438066.2 linkuse as main transcript	n.*10581A>G		non_coding_transcript_exon_variant	11/15	3		ENSP00000388021.2	F6WRY4
SPEN	ENST00000438066.2 linkuse as main transcript	n.*10581A>G		3_prime_UTR_variant	11/15	3		ENSP00000388021.2	F6WRY4

Frequencies

GnomAD3 genomes

AF:

0.0000153

AC:

AN:

65242

Hom.:

Cov.:

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:

0.0000329

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000605

AC:

AN:

693710

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

351402

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000771

Gnomad4 OTH exome

AF:

0.0000350

GnomAD4 genome

AF:

0.0000153

AC:

AN:

65242

Hom.:

Cov.:

AF XY:

0.0000323

AC XY:

AN XY:

30940

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000329

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000879

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.35

DANN

Benign

0.15

DEOGEN2

Benign

0.081

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.25

M_CAP

Benign

0.0027

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.12

REVEL

Benign

0.027

Sift

Benign

1.0

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.045

MutPred

0.17

Loss of glycosylation at T3244 (P = 9e-04);

MVP

0.043

MPC

0.23

ClinPred

0.017

GERP RS

-0.36

Varity_R

0.025

gMVP

0.079

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over