chr14-60645879-T-C

Variant names:

• chr14-60645879-T-C
• rs76116881
• NM_005982.4:c.*404A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_005982.4(SIX1):​c.*404A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 156,466 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (146 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (0 hom.)
• Consequence: SIX1 NM_005982.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.22
• Publications: 1 publications found

Genes affected

SIX1 (HGNC:10887): (SIX homeobox 1) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]

SIX1 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 23

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• branchio-oto-renal syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics
• branchiootic syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• branchiootic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 14-60645879-T-C is Benign according to our data. Variant chr14-60645879-T-C is described in ClinVar as Benign. ClinVar VariationId is 313457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0813 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005982.4. 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
	SIX1	NM_005982.4	MANE Select	c.*404A>G		3_prime_UTR	Exon 2 of 2	NP_005973.1	Q15475
	SIX1	NM_001425142.1		c.*678A>G		3_prime_UTR	Exon 2 of 2	NP_001412071.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX1	ENST00000645694.3	MANE Select	c.*404A>G		3_prime_UTR	Exon 2 of 2	ENSP00000494686.1	Q15475
	SIX1	ENST00000949515.1		c.*404A>G		3_prime_UTR	Exon 2 of 2	ENSP00000619574.1
	SIX1	ENST00000554986.2	TSL:3	c.*404A>G		3_prime_UTR	Exon 2 of 2	ENSP00000452700.2	H0YK85

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3644 AN: 151970 Hom.: 144 Cov.: 33

Gnomad AFR AF: 0.0833

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.00251 AC: 11 AN: 4378 Hom.: 0 Cov.: 0 AF XY: 0.00224 AC XY: 5 AN XY: 2230

African (AFR) AF: 0.0729 AC: 7 AN: 96

American (AMR) AF: 0.00 AC: 0 AN: 334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 96

East Asian (EAS) AF: 0.00 AC: 0 AN: 156

South Asian (SAS) AF: 0.00 AC: 0 AN: 160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 12

European-Non Finnish (NFE) AF: 0.000627 AC: 2 AN: 3190

Other (OTH) AF: 0.00877 AC: 2 AN: 228

GnomAD4 genome AF: 0.0241 AC: 3664 AN: 152088 Hom.: 146 Cov.: 33 AF XY: 0.0228 AC XY: 1698 AN XY: 74372

African (AFR) AF: 0.0836 AC: 3466 AN: 41454

American (AMR) AF: 0.00719 AC: 110 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68016

Other (OTH) AF: 0.0204 AC: 43 AN: 2106

Alfa AF: 0.0150 Hom.: 25

Bravo AF: 0.0274

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nonsyndromic hearing loss 23 (1)
-	-	1	Branchiootic syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs76116881; hg19: chr14-61112597;