rs727503289

Variant names:

• chr22-36300975-C-A
• NM_002473.6:c.2714G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-36300975-C-A
• chr22-36300975-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_002473.6(MYH9):​c.2714G>T​(p.Arg905Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,459,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.0000048 (0 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant in the MYH9 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 84 curated benign missense variants. Gene score misZ: 3.473 (above the threshold of 3.09). Trascript score misZ: 6.1231 (above the threshold of 3.09). GenCC associations: The gene is linked to May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.2714G>T	p.Arg905Leu	missense_variant	Exon 22 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.2714G>T	p.Arg905Leu	missense_variant	Exon 22 of 41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.2777G>T	p.Arg926Leu	missense_variant	Exon 23 of 42			ENSP00000510688.1
MYH9	ENST00000495928.1	n.264G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2
MYH9	ENST00000691109.1	n.3009G>T		non_coding_transcript_exon_variant	Exon 16 of 35

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459380 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.016	D
Sift4G	Benign	0.12	T
Polyphen		0.92	P
Vest4		0.77
MutPred		0.41		Loss of methylation at R903 (P = 0.0421);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.68
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-36697021;