NM_175875.5:c.2215C>A

Variant names:

• chr19-45765506-G-T
• rs139368585
• NM_175875.5:c.2215C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_175875.5(SIX5):​c.2215C>A​(p.Leu739Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85

Genes affected

SIX5 (HGNC:10891): (SIX homeobox 5) The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]

ENSG00000259605 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2969468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5	c.2215C>A	p.Leu739Met	missense_variant	Exon 3 of 3	ENST00000317578.7	NP_787071.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX5	ENST00000317578.7	c.2215C>A	p.Leu739Met	missense_variant	Exon 3 of 3	1	NM_175875.5	ENSP00000316842.4
SIX5	ENST00000560160	c.*425C>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000453239.2
SIX5	ENST00000560168	c.*1641C>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2
ENSG00000259605	ENST00000559756.1	n.722G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251260 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461062 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.67	.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.12	.;N;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;.
Vest4		0.58, 0.51
MutPred		0.21		Gain of solvent accessibility (P = 0.3089);Gain of solvent accessibility (P = 0.3089);.;
MVP		0.85
MPC		0.30
ClinPred		0.71	D
GERP RS		3.4
Varity_R		0.19
gMVP		0.25

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: rs139368585; hg19: chr19-46268764;