9-122227488-A-G

Position:

• chr9-122227488-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_014368.5(LHX6):​c.85-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (0 hom., cov: 30)
  • Exomes 𝑓: 0.017 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: LHX6 NM_014368.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001935
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.769

Genes affected

LHX6 (HGNC:21735): (LIM homeobox 6) This gene encodes a member of a large protein family that contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein has tandem LIM domains as well as a DNA-binding homeodomain. The protein functions as a transcription factor involved in embryogenesis and head development and is highly expressed in neural crest derived mesenchyme cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 9-122227488-A-G is Benign according to our data. Variant chr9-122227488-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 778380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX6	NM_014368.5	c.85-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394319.9	NP_055183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX6	ENST00000394319.9	c.85-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014368.5	ENSP00000377854	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 572 AN: 102138 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.0152

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00568

Gnomad EAS AF: 0.00190

Gnomad SAS AF: 0.00449

Gnomad FIN AF: 0.00495

Gnomad MID AF: 0.00370

Gnomad NFE AF: 0.00687

Gnomad OTH AF: 0.00433

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0169 AC: 4327 AN: 255704 Hom.: 1 Cov.: 0 AF XY: 0.0154 AC XY: 2222 AN XY: 144472

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.00436

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0223

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00560 AC: 572 AN: 102222 Hom.: 0 Cov.: 30 AF XY: 0.00518 AC XY: 254 AN XY: 48994

Gnomad4 AFR AF: 0.00484

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00568

Gnomad4 EAS AF: 0.00190

Gnomad4 SAS AF: 0.00446

Gnomad4 FIN AF: 0.00495

Gnomad4 NFE AF: 0.00687

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00644 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.036
SpliceAI score (max)		0.010		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: rs566350165; hg19: chr9-124989767; COSMIC: COSV61344518; COSMIC: COSV61344518;