22-43976070-A-C

Variant names:

• chr22-43976070-A-C
• rs755098914
• NM_015380.5:c.664A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015380.5(SAMM50):​c.664A>C​(p.Thr222Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T222A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAMM50 NM_015380.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.65
• Publications: 0 publications found

Genes affected

SAMM50 (HGNC:24276): (SAMM50 sorting and assembly machinery component) This gene encodes a component of the Sorting and Assembly Machinery (SAM) of the mitochondrial outer membrane. The Sam complex functions in the assembly of beta-barrel proteins into the outer mitochondrial membrane.[provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015380.5. 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
	SAMM50	NM_015380.5	MANE Select	c.664A>C	p.Thr222Pro	missense	Exon 8 of 15	NP_056195.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMM50	ENST00000350028.5	TSL:1 MANE Select	c.664A>C	p.Thr222Pro	missense	Exon 8 of 15	ENSP00000345445.4	Q9Y512
	SAMM50	ENST00000943220.1		c.766A>C	p.Thr256Pro	missense	Exon 8 of 15	ENSP00000613279.1
	SAMM50	ENST00000854677.1		c.712A>C	p.Thr238Pro	missense	Exon 8 of 15	ENSP00000524736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251088 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1458450 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724836

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

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109174

Other (OTH) AF: 0.00 AC: 0 AN: 60256

⚠️ 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 Cov.: 32

ExAC AF: 0.000107 AC: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.43
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.91	P
Vest4		0.69
MutPred		0.69		Loss of MoRF binding (P = 0.0559)
MVP		0.77
MPC		0.94
ClinPred		0.23	T
GERP RS		5.5
Varity_R		0.66
gMVP		0.69
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs755098914; hg19: chr22-44371950;