17-72121467-A-G

Variant names:

• chr17-72121467-A-G
• rs575451633
• NM_000346.4:c.76A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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)

ENSG00000288605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 700391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX9	NM_000346.4	MANE Select	c.76A>G	p.Met26Val	missense	Exon 1 of 3	NP_000337.1	P48436

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX9	ENST00000245479.3	TSL:1 MANE Select	c.76A>G	p.Met26Val	missense	Exon 1 of 3	ENSP00000245479.2	P48436
	SOX9	ENST00000877559.1		c.76A>G	p.Met26Val	missense	Exon 1 of 3	ENSP00000547618.1
	SOX9-AS1	ENST00000414600.1	TSL:3	n.96+20218T>C		intron	N/A

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

GnomAD2 exomes AF: 0.000551 AC: 135 AN: 244822 AF XY: 0.000695

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.0000448 AC: 2 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00307 AC: 265 AN: 86202

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52496

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000119 AC: 132 AN: 1111800

Other (OTH) AF: 0.000398 AC: 24 AN: 60346

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41520

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Camptomelic dysplasia (1)
-	-	1	not provided (1)
-	-	1	SOX9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.020
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.0
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
Vest4		0.34
MutPred		0.20		Loss of loop (P = 0.0128)
MVP		0.82
MPC		1.1
ClinPred		0.027	T
GERP RS		4.4
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.39
gMVP		0.49
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

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