chr17-18120815-C-G

Variant names:

• chr17-18120815-C-G
• rs876657897
• NM_016239.4:c.2015C>G
• MYO15A p.Ser672Cys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_016239.4(MYO15A):c.2015C>G (p.Ser672Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000736 (AC=9) in the gnomAD database across 1,222,020 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000012. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S672P: Likely_benign (ClinVar VariationId 1198834, 2 stars); p.S672= (synonymous): Likely_benign (ClinVar VariationId 2965797, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.544
• Publications: 0 publications found

Genes affected

MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

MYO15A Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MYO15A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000012 — very rare for AR gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYO15A NM_016239.4	MANE Select	c.2015C>G p.Ser672Cys	missense	Exon 2 of 66	Prot: NP_057323.3

MYO15A NM_016239.4

MANE Select

HGVSc / HGVSpc.2015C>Gp.Ser672Cys

Exon rankExon 2 of 66

missense

Prot: NP_057323.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYO15A ENST00000647165.2	MANE Select	c.2015C>G p.Ser672Cys	missense	Exon 2 of 66	Prot: ENSP00000495481.1 UniProt:
	MYO15A ENST00000583079.1	TSL:6	n.1648C>G	non_coding_transcript_exon	Exon 1 of 1	Prot:

MYO15A ENST00000647165.2

MANE Select

HGVSc / HGVSpc.2015C>Gp.Ser672Cys

Exon rankExon 2 of 66

missense

Prot: ENSP00000495481.1UniProt: Q9UKN7-1

MYO15A ENST00000583079.1

TSL:6

HGVSc / HGVSpn.1648C>G

Exon rankExon 1 of 1

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000203	AC:3	Hom:0	AN:147698	Cov:32
GnomAD4 exome	AF: 0.00000558	AC:6	Hom:0	AN:1074322	Cov:32
GnomAD4 genome	AF: 0.0000203	AC:3	Hom:0	AN:147698	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000594	AC:1	Hom:0	AN:16840	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000203	1	49254	0.00	0	67116

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
FuncVEP CTI	Benign	0.0077
GPN-Star LLR	N/A	-1.9
GPN-Star score	N/A	1.9
LIST_S2	Benign	0.21	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.76	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Benign	0.0	N
PhyloP100	Benign	-0.54
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.097
Sift	Benign	0.067	T
Sift4G	Uncertain	0.015	D
Varity_R	N/A	0.080
VESM-3B	Benign	-4.7

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs876657897;

hg19: chr17-18024129;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar