rs879255648

Variant names:

• chr3-128060598-A-G
• rs879255648
• NM_013336.4:c.553A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_013336.4(SEC61A1):​c.553A>G​(p.Thr185Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T185S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC61A1 NM_013336.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.28
• Publications: 10 publications found

Genes affected

SEC61A1 (HGNC:18276): (SEC61 translocon subunit alpha 1) The protein encoded by this gene belongs to the SECY/SEC61- alpha family. It appears to play a crucial role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. This protein found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins. This gene encodes an alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits. [provided by RefSeq, Jul 2008]

SEC61A1 Gene-Disease associations (from GenCC):

• hyperuricemic nephropathy, familial juvenile type 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• immunodeficiency, common variable, 15

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• SEC61A1 deficiency

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

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.
• PP5: Variant 3-128060598-A-G is Pathogenic according to our data. Variant chr3-128060598-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 253146.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013336.4. 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
	SEC61A1	NM_013336.4	MANE Select	c.553A>G	p.Thr185Ala	missense	Exon 7 of 12	NP_037468.1	B3KNF6
	SEC61A1	NM_001400328.1		c.571A>G	p.Thr191Ala	missense	Exon 7 of 12	NP_001387257.1	B4DR61
	SEC61A1	NM_001400329.1		c.394A>G	p.Thr132Ala	missense	Exon 6 of 11	NP_001387258.1	C9JXC6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC61A1	ENST00000243253.8	TSL:1 MANE Select	c.553A>G	p.Thr185Ala	missense	Exon 7 of 12	ENSP00000243253.3	P61619-1
	SEC61A1	ENST00000483956.2	TSL:1	n.553A>G		non_coding_transcript_exon	Exon 7 of 14	ENSP00000514247.1	A0A8V8TNG8
	SEC61A1	ENST00000937479.1		c.553A>G	p.Thr185Ala	missense	Exon 7 of 13	ENSP00000607538.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperuricemic nephropathy, familial juvenile type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.69
Sift	Benign	0.12	T
Sift4G	Benign	0.42	T
Polyphen		0.021	B
Vest4		0.75
MutPred		0.60		Gain of glycosylation at S180 (P = 0.4269)
MVP		0.92
MPC		1.2
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: 1

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

Other links and lift over

dbSNP: rs879255648; hg19: chr3-127779441; COSMIC: COSV54579523; COSMIC: COSV54579523;