11-9295280-G-C

Variant names:

• chr11-9295280-G-C
• rs138570403
• NM_015012.4:c.347C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015012.4(TMEM41B):​c.347C>G​(p.Ala116Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A116V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM41B NM_015012.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95
• Publications: 1 publications found

Genes affected

TMEM41B (HGNC:28948): (transmembrane protein 41B) Involved in autophagosome assembly. Located in endoplasmic reticulum membrane and mitochondria-associated endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015012.4. 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
	TMEM41B	NM_015012.4	MANE Select	c.347C>G	p.Ala116Gly	missense	Exon 3 of 7	NP_055827.1	Q5BJD5-1
	TMEM41B	NM_001165030.3		c.347C>G	p.Ala116Gly	missense	Exon 3 of 3	NP_001158502.1	Q5BJD5-3
	TMEM41B	NR_028491.3		n.499C>G		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM41B	ENST00000528080.6	TSL:1 MANE Select	c.347C>G	p.Ala116Gly	missense	Exon 3 of 7	ENSP00000433126.1	Q5BJD5-1
	TMEM41B	ENST00000611268.4	TSL:1	c.347C>G	p.Ala116Gly	missense	Exon 3 of 8	ENSP00000480141.1	Q5BJD5-1
	TMEM41B	ENST00000299596.8	TSL:1	n.347C>G		non_coding_transcript_exon	Exon 3 of 8	ENSP00000299596.4	Q5BJD5-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 220394 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419766 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 706050

African (AFR) AF: 0.00 AC: 0 AN: 32266

American (AMR) AF: 0.00 AC: 0 AN: 39544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39216

South Asian (SAS) AF: 0.00 AC: 0 AN: 81592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5164

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086068

Other (OTH) AF: 0.00 AC: 0 AN: 58670

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Benign	0.93
DEOGEN2	Benign	0.0032	T
Eigen	Benign	0.060
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N
PhyloP100		9.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	1.4	N
REVEL	Benign	0.24
Sift	Benign	0.98	T
Sift4G	Benign	0.71	T
Polyphen		0.0040	B
Vest4		0.76
MutPred		0.44		Loss of catalytic residue at A116 (P = 0.0429)
MVP		0.55
MPC		0.24
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.22
gMVP		0.76
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: 5

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

Other links and lift over

dbSNP: rs138570403; hg19: chr11-9316827;