17-72121467-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000346.4(SOX9):c.76A>G(p.Met26Val) variant causes a missense change. The variant allele was found at a frequency of 0.000274 in 1,612,664 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. M26K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (16 hom.)
• Consequence: SOX9 NM_000346.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.01

Genes affected

SOX9 (HGNC:11204): (SRY-box transcription factor 9) The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal. [provided by RefSeq, Jul 2008]

SOX9-AS1 (HGNC:49321): (SOX9 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009490371).
• BP6: Variant 17-72121467-A-G is Benign according to our data. Variant chr17-72121467-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 700391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-72121467-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX9	NM_000346.4	c.76A>G	p.Met26Val	missense_variant	1/3	ENST00000245479.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX9	ENST00000245479.3	c.76A>G	p.Met26Val	missense_variant	1/3	1	NM_000346.4	P1
SOX9-AS1	ENST00000414600.1	n.96+20218T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151986 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000551 AC: 135 AN: 244822 Hom.: 5 AF XY: 0.000695 AC XY: 93 AN XY: 133760

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00321

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000836

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1460560 Hom.: 16 Cov.: 31 AF XY: 0.000416 AC XY: 302 AN XY: 726616

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00307

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000627 AC: 76

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SOX9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Camptomelic dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

SOX9: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D
Eigen	Benign	0.020
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0095	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.022	D;.
Sift4G	Benign	0.078	T;.
Polyphen		0.041	B;B
Vest4		0.34
MutPred		0.20		Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP		0.82
MPC		1.1
ClinPred		0.027	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.39
gMVP		0.49

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: rs575451633; hg19: chr17-70117608; COSMIC: COSV55425301; COSMIC: COSV55425301;