4-144114760-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002099.8(GYPA):c.365C>T(p.Pro122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P122S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GYPA NM_002099.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.348

Genes affected

GYPA (HGNC:4702): (glycophorin A (MNS blood group)) Glycophorins A (GYPA) and B (GYPB) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups. In addition to the M or N and S or s antigens that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include all the variants of the Miltenberger complex and several isoforms of Sta, as well as Dantu, Sat, He, Mg, and deletion variants Ena, S-s-U- and Mk. Most of the variants are the result of gene recombinations between GYPA and GYPB. [provided by RefSeq, Jul 2008]

LOC105377460 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYPA	NM_002099.8	c.365C>T	p.Pro122Leu	missense_variant	6/7	ENST00000641688.3
LOC105377460	XR_002959803.2	n.4801G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYPA	ENST00000641688.3	c.365C>T	p.Pro122Leu	missense_variant	6/7		NM_002099.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.365C>T (p.P122L) alteration is located in exon 6 (coding exon 6) of the GYPA gene. This alteration results from a C to T substitution at nucleotide position 365, causing the proline (P) at amino acid position 122 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	1.5
Dann	Benign	0.89
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.69	T;.;T;T;.;.;T;T;T;T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.097	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.21	T
Sift4G	Uncertain	0.011	D;.;T;D;.;D;.;.;D;T;T;D
Polyphen		0.072, 0.0050	.;.;.;.;.;.;.;.;B;B;B;.
Vest4		0.065
MutPred		0.61		.;Loss of glycosylation at P122 (P = 0.0311);Loss of glycosylation at P122 (P = 0.0311);.;.;.;.;.;.;.;.;.;
MVP		0.055
MPC		0.025
ClinPred		0.071	T
GERP RS		0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.012

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 7

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: chr4-145035913;