3-108383733-T-A

Variant names:

• chr3-108383733-T-A
• rs79837783
• NM_014981.3:c.5632-4A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_014981.3(MYH15):​c.5632-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00077 in 1,033,904 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.0017 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00077 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH15 NM_014981.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007305
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.369
• Publications: 1 publications found

Genes affected

MYH15 (HGNC:31073): (myosin heavy chain 15) Predicted to enable several functions, including ATP binding activity; actin filament binding activity; and calmodulin binding activity. Predicted to be involved in extraocular skeletal muscle development. Located in cytosol and intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

LOC124900545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 3-108383733-T-A is Benign according to our data. Variant chr3-108383733-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 711388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014981.3. 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
	MYH15	NM_014981.3	MANE Select	c.5632-4A>T		splice_region intron	N/A	NP_055796.2	A0A8I5KXJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH15	ENST00000693548.1	MANE Select	c.5632-4A>T		splice_region intron	N/A	ENSP00000508967.1	Q9Y2K3
	MYH15	ENST00000273353.5	TSL:1	c.5632-4A>T		splice_region intron	N/A	ENSP00000273353.4	Q9Y2K3
	MYH15	ENST00000689784.1		c.4651-4A>T		splice_region intron	N/A	ENSP00000509841.1	A0A8I5KYE8

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 98 AN: 59174 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.000607

Gnomad AMI AF: 0.00301

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.00172

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00320

Gnomad FIN AF: 0.00665

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00135

GnomAD2 exomes AF: 0.00208 AC: 117 AN: 56170 AF XY: 0.00232

Gnomad AFR exome AF: 0.000459

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.00115

Gnomad EAS exome AF: 0.00410

Gnomad FIN exome AF: 0.00498

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000770 AC: 796 AN: 1033904 Hom.: 1 Cov.: 30 AF XY: 0.000912 AC XY: 462 AN XY: 506446

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000472 AC: 12 AN: 25422

American (AMR) AF: 0.00397 AC: 64 AN: 16130

Ashkenazi Jewish (ASJ) AF: 0.00216 AC: 32 AN: 14788

East Asian (EAS) AF: 0.00111 AC: 30 AN: 27014

South Asian (SAS) AF: 0.00378 AC: 144 AN: 38062

European-Finnish (FIN) AF: 0.00214 AC: 60 AN: 28050

Middle Eastern (MID) AF: 0.00171 AC: 5 AN: 2930

European-Non Finnish (NFE) AF: 0.000497 AC: 417 AN: 839326

Other (OTH) AF: 0.000759 AC: 32 AN: 42182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00165 AC: 98 AN: 59226 Hom.: 0 Cov.: 17 AF XY: 0.00168 AC XY: 47 AN XY: 27972

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000605 AC: 14 AN: 23158

American (AMR) AF: 0.00106 AC: 5 AN: 4696

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 2 AN: 1164

East Asian (EAS) AF: 0.00 AC: 0 AN: 990

South Asian (SAS) AF: 0.00323 AC: 4 AN: 1240

European-Finnish (FIN) AF: 0.00665 AC: 17 AN: 2558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.00223 AC: 54 AN: 24264

Other (OTH) AF: 0.00134 AC: 1 AN: 744

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.044
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: rs79837783; hg19: chr3-108102580; COSMIC: COSV56310773;